Heterocyclic compound derivatives and medicines

ABSTRACT

The present invention provides a compound which is useful as a PGI&lt;SUB&gt;2 &lt;/SUB&gt;receptor agonist, and a pharmaceutical composition.

TECHNICAL FIELD

The present invention relates to a novel heterocyclic derivative whichis useful as a medicine, or a salt thereof, and a PGI₂ receptor agonistcontaining the same as an active ingredient.

BACKGROUND ART

Prostaglandin I₂ (PGI₂) is produced from arachidonic acid viaprostaglandin H₂ (PGH₂) in the living body and has various potentpharmacological effects such as inhibition of platelet aggregation,vasodilation, inhibition of lipid deposition, and inhibition ofleucocyte activation. It is therefore considered that PGI₂ is effectivefor treatment of peripheral vascular diseases (for example,arteriosclerosis obliterans, intermittent claudication, peripheralarterial embolism, vibration disease, and Raynaud's disease), systemiclupus erythematosus, reocclusion or restenosis after percutaneoustransluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis,diabetic neuropathy, diabetic nephropathy, hypertension, ischemicdiseases (for example, cerebral infarction and myocardial infarction),transient ischemic attack and glomerulonephritis, or acceleration ofangiogenesis in peripheral blood vessel reconstruction technique orangiogenesis therapy.

However, PGI₂ is not suited for use as a medicine because it ischemically unstable and has very short biological half-life, and alsohas such a problem that side effect is likely to arise because it isdifficult to separate the desired effect from the other effect. For thepurpose of persistence of drug efficacy, relief of side effect andimprovement of compliance, long acting preparations of prostaglandinshave been researched and developed. However, satisfactory results havenever been achieved.

Under these circumstances, it is expected that a PGI₂ receptor agonist,which is non-prostanoid and has excellent affinity to PGI₂ receptor andchemical stability, exerts excellent therapeutic effect a medicine ascompared with conventional PGI₂ preparations, and thus it hasintensively been researched and developed.

For example, it has been known that imidazole derivatives (Br. J.Pharmcol., 102, 251 (1991)), oxazole derivatives (J. Med. Chem., 35,3498 (1992), J. Med. Chem., 36, 3884 (1993)), pyrazole derivatives(Folia Phermacol. Jp., 106, 181 (1995), Bioorg. Med. Chem. Lett., 5,1071 (1995), Bioorg. Med. Chem. Lett., 5, 1083 (1995)), pyrazinonederivatives (Bioorg. Med. Chem. Lett., 10, 2787 (2000)) and oximederivatives (Folia Phermacol. Jp., 106, 181 (1995), Bioorg. Med. Chem.Lett., 5, 1071 (1995), Bioorg. Med. Chem. Lett., 5, 1083 (1995)) havePGI₂ receptor agonistic activity.

Also it is known that 2,3-diphenylpyrazine derivatives (JapaneseUnexamined Patent Publication No. Hei-7-33752) have a herbicidal effect,2,3-diphenylpyridine derivatives and 5,6-diphenylpyrimidine derivatives(WO92/01675) have a leukotriene B₄ antagonism and 2,3-diphenylpyridinederivatives (WO96/18616) have a nitric oxide synthesis inhibitoryeffect. However, it is not known that these compounds have a PGI₂receptor agonistic activity.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a novel PGI₂ receptoragonist and a novel heterocyclic derivative.

To achieve the above object, the present inventors have synthesizedvarious compounds during the process of study and found thatheterocyclic derivatives represented by the following general formula(1) (hereinafter also referred to as heterocyclic derivatives (1)) haveexcellent PGI₂ receptor agonistic activity, and thus the presentinvention has been completed.

wherein R¹ and R² are the same or different and each represents anoptionally substituted aryl, and the substituents are the same ordifferent and 1 to 3 substituents are selected from the group consistingof halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl,alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy,cyano and nitro,

Y represents N, N→O or CR⁵, Z represents N or CR⁶; and R⁵ and R⁶ are thesame or different and each represents hydrogen, alkyl or halogen,

A represents NR⁷, O, S, SO, SO₂, or ethylene, and R⁷ representshydrogen, alkyl, alkenyl or cycloalkyl,

D represents alkylene or alkenylene which are optionally substitutedwith hydroxy, or A and D are combined with each other to form a divalentgroup represented by the following formula (2):

r represents an integer of 0 to 2, q represents an integer of 2 to 3,and t represents an integer of 0 to 4,

E represents phenylene or single bond, or D and E are combined with eachother to form a divalent group represented by the following formula (3):

u represents an integer of 0 to 2, and v represents 0 or 1,

G represents O, S, SO, SO₂, or C(R⁸)(R⁹), and R⁸ and R⁹ are the same ordifferent and each represents hydrogen or alkyl,

R³ and R⁴ are the same or different and each represents hydrogen oralkyl,

Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl,monoalkylcarbamoyl, dialkylcarbamoyl, or a group represented by thefollowing formula (22):

R¹⁰ represents amino, monoalkylamino, dialkylamino, hydroxy, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaryloxy, or optionally substituted heterocyclic group, and thesubstituents of alkyl, aryl, aryloxy or heterocyclic group are the sameor different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro.

Among the heterocyclic derivatives represented by the formula (1),preferable compounds are the following compounds wherein R¹ and R² arethe same or different and each represents optionally substituted phenyl,and the substituents are the same or different and 1 to 3 substituentsare selected from the group consisting of halogen, alkyl and alkoxy,

Y and Z correspond to either of the following cases (1) and (2):

(1) Y is N or CH, and Z is N or CH, and

(2) Y is N→O, and Z is CH,

A represents NR⁷, and R⁷ represents hydrogen, alkyl, or cycloalkyl,

D represents alkylene or alkenylene,

E represents single bond,

G represents O, S, SO, SO₂, or C(R⁸)(R⁹), and R⁸ and R⁹ each representshydrogen,

R³ and R⁴ are the same or different and each represents hydrogen oralkyl, and

Q represents carboxy, alkoxycarbonyl, tetrazolyl, or a group representedby the formula (22), and R¹⁰ represents amino, monoalkylamino,dialkylamino, hydroxy, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted aryloxy, or optionallysubstituted heterocyclic group, and the substituents of alkyl, aryl,aryloxy or heterocyclic group are the same or different and 1 to 3substituents selected from the group consisting of halogen, alkyl,haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl,hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro.

Among the heterocyclic derivatives represented by the formula (1), morepreferable compounds are the following compounds wherein R¹ and R² arethe same or different and each represents optionally substituted phenyl,and the substituents are the same or different and 1 to 3 substituentsare selected from the group consisting of halogen, alkyl and alkoxy,

Y and Z correspond to either of the following cases (1) and (2):

(1) Y is N, and Z is CH, and

(2) Y is CH, and Z is N or CH,

A represents NR⁷, and R⁷ represents hydrogen or alkyl,

D represents alkylene,

E represents single bond,

G represents O,

R³ and R⁴ are the same or different and each represents hydrogen oralkyl,

Q represents carboxy, tetrazolyl, or a group represented by the formula(22), and R¹⁰ represents amino, mono alkylamino, dialkylamino, hydroxy,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted aryloxy, or optionally substituted heterocyclic group, andthe substituents of alkyl, aryl, aryloxy or heterocyclic group are thesame or different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro.

Among the heterocyclic derivatives represented by the formula (1),particularly preferable compounds are the following compounds wherein R¹and R² are the same or different and each represents optionallysubstituted phenyl, and the substituents are the same or different and 1to 3 substituents are selected from the group consisting of halogen,alkyl and alkoxy,

Y represents N, and Z represents CH,

A represents NR⁷, and R⁷ represents alkyl,

D represents alkylene,

E represents single bond,

G represents O,

R³ and R⁴ are the same or different and each represents hydrogen oralkyl, and

Q represents carboxy or a group represented by the formula (22), and R¹⁰represents amino monoalkylamino, dialkylamino, hydroxy, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaryloxy or optionally substituted heterocyclic group, and thesubstituents of alkyl, aryl, aryloxy or heterocyclic group are the sameor different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro.

Specific examples of preferable compounds among the heterocyclicderivatives represented by the formula (1) include the followingcompounds (1) to (32):

-   (1)    2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]butyloxy}acetic    acid,-   (2) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]butyloxy}acetic    acid,-   (3)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic    acid,-   (4)    2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic    acid,-   (5)    2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methylamino}pyrazine    1-oxide,-   (6)    2-{4-[N-(4,5-di-p-tolylpyrimidin-2-yl)-N-methylamino]butyloxy}acetic    acid,-   (7) 7-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]heptanoic acid,-   (8)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio}acetic    acid,-   (9)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(Z)-2-buten-1-yloxy}acetic    acid,-   (10)    2-{4-[N-(5,6-di-p-tolyl-1,2,4-triazin-3-yl)-N-isopropylamino]butyloxy}acetic    acid,-   (11) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-ethylamino]butyloxy}acetic    acid,-   (12)    2-{4-[N-(2,3-diphenylpyridin-6-yl)-N-methylamino]butyloxy}acetic    acid,-   (13)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfinyl}acetic    acid,-   (14)    2-{4-[N-(5,6-diphenyl-1,2,4-triazin-3-yl)-N-methylamino]butyloxy}acetic    acid,-   (15)    2-{4-[N-(4,5-diphenylpyrimidin-2-yl)-N-methylamino]butyloxy}acetic    acid,-   (16)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(p-toluenesulfonyl)acetamide,-   (17)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(isopropylsulfonyl)acetamide,-   (18)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(trifluoromethanesulfonyl)acetamide,-   (19)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(o-toluenesulfonyl)acetamide,-   (20)    N-(benzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,-   (21)    N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,-   (22)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-methoxybenzenesulfonyl)acetamide,-   (23)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-fluorobenzenesulfonyl)acetamide,-   (24)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(2-thiophenesulfonyl)acetamide,-   (25)    N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,-   (26)    N-(N,N-dimethylaminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,-   (27)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(morpholin-4-ylsulfonyl)acetamide,-   (28)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(pyrrolidin-1-ylsulfonyl)acetamide,-   (29)    N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic    acid phenyl ester,-   (30)    N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic    acid,-   (31)    N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic    acid sodium salt, and-   (32)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.

Heterocyclic derivatives represented by the following general formula(1z) wherein substituents correspond to any one of the following cases(I) to (V) (hereinafter also referred to as heterocyclic derivatives(1z)) are novel compounds which have never been described in documents.

(I)

R⁹¹ and R⁹² are the same or different and each represents optionallysubstituted aryl, and the substituents are the same or different and 1to 3 substituents are selected from the group consisting of halogen,alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl,alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy,cyano and nitro,

Y⁹ represents N or N→O, Z⁹ represents N or CR⁹⁶, and R⁹⁶ representshydrogen, alkyl, or halogen,

A⁹ represents NR⁹⁷, O, S, SO, SO₂, or ethylene, and R⁹⁷ representshydrogen, alkyl, alkenyl, or cycloalkyl

D⁹ represents alkylene or alkenylene which are optionally substitutedwith hydroxy, or A⁹ and D⁹ are combined with each other to form adivalent group represented by the following formula (2z):

m represents an integer of 0 to 2, k represents an integer of 2 to 3,and n represents an integer of 0 to 4,

E⁹ represents phenylene or single bond, or D⁹ and E⁹ are combined witheach other to form a divalent group represented by the following formula(3z):

w represents an integer of 0 to 2, and x represents 0 or 1,

G⁹ represents O, S, SO, SO₂, or C(R⁹⁸)(R⁹⁹), and R⁹⁸ and R⁹⁹ are thesame or different and each represents hydrogen or alkyl,

R⁹³ and R⁹⁴ are the same or different and each represents hydrogen oralkyl,

Q⁹ represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl,monoalkylcarbamoyl, dialkylcarbamoyl, or a group represented by the

following formula (22z):

R⁹¹⁰ represents amino, monoalkylamino, dialkylamino, hydroxy, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaryloxy, or optionally substituted heterocyclic group, and thesubstituents of alkyl, aryl, aryloxy or heterocyclic group are the sameor different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro;

(II)

R⁹¹ and R⁹² are the same or different and each represents optionallysubstituted aryl, and the substituents are the same or different and 1to 3 substituents are selected from the group consisting of halogen,alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl,alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy,cyano and nitro,

Y⁹ represents CR⁹⁵, Z⁹ represents N or CR⁹⁶, and R⁹⁵ and R⁹⁶ are thesame or different and each represents hydrogen, alkyl, or halogen,

A⁹ represents SO or SO₂,

D⁹ represents alkylene or alkenylene which are optionally substitutedwith hydroxy, or A⁹ and D⁹ are combined with each other to form adivalent group represented by the following formula (2z):

m represents an integer of 0 to 2, k represents an integer of 2 to 3,and n represents an integer of 0 to 4,

E⁹ represents phenylene or single bond, or D⁹ and E⁹ are combined witheach other to form a divalent group represented by the following formula(3z):

w represents an integer of 0 to 2, and x represents 0 or 1,

G⁹ represents O, S, SO, SO₂, or C(R⁹⁸)(R⁹⁹), and R⁹⁸ and R⁹⁹ are thesame or different and each represents hydrogen or alkyl,

R⁹³ and R⁹⁴ are the same or different and each represents hydrogen oralkyl,

Q⁹ represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl,monoalkylcarbamoyl, dialkylcarbamoyl, or a group represented by thefollowing formula (22z):

R⁹¹⁰ represents amino, monoalkylamino, dialkylamino, hydroxy, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaryloxy, or optionally substituted heterocyclic group, and thesubstituents of alkyl, aryl, aryloxy or heterocyclic group are the sameor different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro;

(III)

R⁹¹ and R⁹² are the same or different and each represents optionallysubstituted aryl, and the substituents are the same or different and 1to 3 substituents are selected from the group consisting of halogen,alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl,alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy,cyano and nitro,

Y⁹ represents CR⁹⁵, Z⁹ represents N or CR⁹⁶, and R⁹⁵ and R⁹⁶ are thesame or different and each represents hydrogen, alkyl, or halogen,

A⁹ represents NR⁹⁷, O, S, or ethylene, and R⁹⁷ represents hydrogen,alkyl, alkenyl, or cycloalkyl,

D⁹ represents alkenylene, or A⁹ and D⁹ are combined with each other toform a divalent group represented by the following formula (2z):

m represents an integer of 0 to 2, k represents an integer of 2 to 3,and n represents an integer of 0 to 4,

E⁹ represents phenylene or single bond, or D⁹ and E⁹ are combined witheach other to form a divalent group represented by the following formula(3z):

w represents an integer of 0 to 2, and x represents 0 or 1,

G⁹ represents O, S, SO, SO₂ or C(R⁹⁸)(R⁹⁹), and R⁹⁸, R⁹⁹ are the same ordifferent and each represents hydrogen or alkyl,

R⁹³ and R⁹⁴ are the same or different and each represents hydrogen oralkyl,

Q⁹ represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl,monoalkylcarbamoyl, dialkylcarbamoyl, or a group represented by thefollowing formula (22z):

R⁹¹⁰ represents amino, monoalkylamino, dialkylamino, hydroxy, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaryloxy, or optionally substituted heterocyclic group, and thesubstituents of alkyl, aryl, aryloxy or heterocyclic group are the sameor different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro;

(IV)

R⁹¹ and R⁹² are the same or different and each represents optionallysubstituted aryl, and the substituents are the same or different and 1to 3 substituents are selected from the group consisting of halogen,alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl,alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy,cyano and nitro,

Y⁹ represents CR⁹⁵, Z⁹ represents N or CR⁹⁶, and R⁹⁵ and R⁹⁶ are thesame or different and each represents hydrogen, alkyl, or halogen,

A⁹ represents NR⁹⁷, O, S, or ethylene, and R⁹⁷ represents hydrogen,alkyl, alkenyl, or cycloalkyl,

D⁹ represents alkylene which is optionally substituted with hydroxy,

E⁹ represents phenylene,

G⁹ represents O, S, SO, SO₂, or C(R⁹⁸)(R⁹⁹), and R⁹⁸ and R⁹⁹ are thesame or different and each represents hydrogen or alkyl,

R⁹³ and R⁹⁴ are the same or different and each represents hydrogen oralkyl,

Q⁹ represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl,monoalkylcarbamoyl, dialkylcarbamoyl, or a group represented by thefollowing formula (22z):

R⁹¹⁰ represents amino, monoalkylamino, dialkylamino, hydroxy, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaryloxy, or optionally substituted heterocyclic group, and thesubstituents of alkyl, aryl, aryloxy or heterocyclic group are the sameor different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro; and

(V)

R⁹¹ and R⁹² are the same or different and each represents optionallysubstituted phenyl, and the substituents are the same or different and 1to 3 substituents are selected from the group consisting of halogen,alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, hydroxy,amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro,

Y⁹ represents CR⁹⁵, Z⁹ represents N or CR⁹⁶, and R⁹⁵ and R⁹⁶ eachrepresents hydrogen,

A⁹ represents NR⁹⁷, and R⁹⁷ represents hydrogen, alkyl, alkenyl, orcycloalkyl,

D⁹ represents alkylene which is optionally substituted with hydroxy,

E⁹ represents single bond,

G⁹ represents O,

R⁹³ and R⁹⁴ are the same or different and each represents hydrogen oralkyl,

Q⁹ represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl,monoalkylcarbamoyl, dialkylcarbamoyl, or a group represented by thefollowing formula (22z):

and R⁹¹⁰ represents amino, monoalkylamino, dialkylamino, hydroxy,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted aryloxy, or optionally substituted heterocyclic group, andthe substituents of alkyl, aryl, aryloxy or heterocyclic group are thesame or different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro.

Among novel heterocyclic derivatives (1z) described above, preferablecompounds are the following compounds wherein substituents correspond toany one of the following cases (i) to (iii):

(i)

R⁹¹ and R⁹² are the same or different and each represents optionallysubstituted phenyl, and the substituents are the same or different and 1to 3 substituents are selected from the group consisting of halogen,alkyl and alkoxy,

Y⁹ and Z⁹ correspond to either of the following cases (1) and (2):

(1) Y⁹ is N, and Z⁹ is N or CH, and

(2) Y⁹ is N→O, and Z⁹ is CH,

A⁹ represents NR⁹⁷, and R⁹⁷ represents hydrogen, alkyl, or cycloalkyl,

D⁹ represents alkylene,

E⁹ represents single bond,

G⁹ represents O, S, SO, SO₂, or C(R⁹⁸)(R⁹⁹), and R⁹⁸ and R⁹⁹ eachrepresents hydrogen,

R⁹³ and R⁹⁴ are the same or different and each represents hydrogen oralkyl, and

Q⁹ represents carboxy, alkoxycarbonyl, tetrazolyl, or a grouprepresented by the formula (22z), R⁹¹⁰ represents amino, monoalkylamino,dialkylamino, hydroxy, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted aryloxy, or optionallysubstituted heterocyclic group, and the substituents of alkyl, aryl,aryloxy or heterocyclic group are the same or different and 1 to 3substituents are selected from the group consisting of halogen, alkyl,haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl,hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro;

(ii)

R⁹¹ and R⁹² are the same or different and each represents optionallysubstituted phenyl, and the substituents are the same or different and 1to 3 substituents are selected from the group consisting of halogen,alkyl and alkoxy,

Y⁹ represents CH, and Z⁹ represents N or CH,

A⁹ represents NR⁹⁷, and R⁹⁷ represents hydrogen, alkyl, or cycloalkyl,

D⁹ represents alkylene,

E⁹ represents single bond,

G⁹ represents O,

R⁹³ and R⁹⁴ are the same or different and each represents hydrogen oralkyl,

Q⁹ represents carboxy, alkoxycarbonyl, tetrazolyl, or a grouprepresented by the formula (22z), R⁹¹⁰ represents amino, monoalkylamino,dialkylamino, hydroxy, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted aryloxy, or optionallysubstituted heterocyclic group, and the substituents of alkyl, aryl,aryloxy or heterocyclic group are the same or different and 1 to 3substituents are selected from the group consisting of halogen, alkyl,haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl,hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro;and

(iii)

R⁹¹ and R⁹² are the same or different and each represents optionallysubstituted phenyl, and the substituents are the same or different and 1to 3 substituents are selected from the group consisting of halogen,alkyl and alkoxy,

Y⁹ and Z⁹ correspond to either of the following cases (1) and (2):

(1) Y⁹ is N or CH, and Z⁹ is N or CH, and

(2) Y⁹ is N→O, and Z⁹ is CH,

A⁹ represents NR⁹⁷, and R⁹⁷ represents hydrogen, alkyl, or cycloalkyl,

D⁹ represents alkenylene,

E⁹ represents single bond,

G⁹ represents O, S, SO, SO₂, or C(R⁹⁸)(R⁹⁹), and R⁹⁸ and R⁹⁹ eachrepresents hydrogen,

R⁹³ and R⁹⁴ are the same or different and each represents hydrogen oralkyl,

Q⁹ represents carboxy, alkoxycarbonyl, tetrazolyl, or a grouprepresented by the formula (22z), R⁹¹⁰ represents amino, monoalkylamino,dialkylamino, hydroxy, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted aryloxy, or optionallysubstituted heterocyclic group, and the substituents of alkyl, aryl,aryloxy or heterocyclic group are the same or different and 1 to 3substituents are selected from the group consisting of halogen, alkyl,haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl,hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro.

Among novel heterocyclic derivatives (1z) described above, morepreferable compounds are the following compounds wherein R⁹¹ and R⁹² arethe same or different and each represents optionally substituted phenyl,and the substituents are the same or different and 1 to 3 substituentsare selected from the group consisting of halogen, alkyl and alkoxy,

Y⁹ and Z⁹ correspond to either of the following cases (1) and (2):

(1) Y⁹ is N, and Z⁹ is CH,

(2) Y⁹ is CH, and Z⁹ is N or CH,

A⁹ represents NR⁹⁷, and R⁹⁷ represents hydrogen or alkyl,

D⁹ represents alkylene,

E⁹ represents single bond,

G⁹ represents O,

R⁹³ and R⁹⁴ are the same or different and each represents hydrogen oralkyl,

Q⁹ represents carboxy, tetrazolyl, or a group represented by the formula(22z), R⁹¹⁰ represents amino, monoalkylamino, dialkylamino, hydroxy,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted aryloxy, or optionally substituted heterocyclic group, andthe substituents of alkyl, aryl, aryloxy or heterocyclic group are thesame or different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro.

Among novel heterocyclic derivatives (1z) described above, particularlypreferable compounds are the following compounds wherein R⁹¹ and R⁹² arethe same or different and each represents optionally substituted phenyl,and the substituents are the same or different and 1 to 3 substituentsare selected from the group consisting of halogen, alkyl and alkoxy,

Y⁹ represents N, and Z⁹ represents CH,

A⁹ represents NR⁹⁷, and R⁹⁷ represents alkyl,

D⁹ represents alkylene,

E⁹ represents single bond,

G⁹ represents O,

R⁹³ and R⁹⁴ are the same or different and each represents hydrogen oralkyl,

Q⁹ represents carboxy or a group represented by the formula (22z), R⁹¹⁰represents amino, monoalkylamino, dialkylamino, hydroxy, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaryloxy, or optionally substituted heterocyclic group, and thesubstituents of alkyl, aryl, aryloxy or heterocyclic group are the sameor different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro.

Specific examples of preferable compounds among novel heterocyclicderivatives (1z) described above include the following compounds (1) to(32):

-   (1)    2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]butyloxy}acetic    acid,-   (2) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]butyloxy}acetic    acid,-   (3)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic    acid,-   (4)    2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic    acid,-   (5)    2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methylamino}pyrazine    1-oxide,-   (6)    2-{4-[N-(4,5-di-p-tolylpyrimidin-2-yl)-N-methylamino]butyloxy}acetic    acid,-   (7) 7-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]heptanoic acid,-   (8)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio}acetic    acid,-   (9)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(Z)-2-buten-1-yloxy}acetic    acid,-   (10)    2-{4-[N-(5,6-di-p-tolyl-1,2,4-triazin-3-yl)-N-isopropylamino]butyloxy}acetic    acid,-   (11) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-ethylamino]butyloxy}acetic    acid,-   (12)    2-{4-[N-(2,3-diphenylpyridin-6-yl)-N-methylamino]butyloxy}acetic    acid,-   (13)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfinyl}acetic    acid,-   (14)    2-{4-[N-(5,6-diphenyl-1,2,4-triazin-3-yl)-N-methylamino]butyloxy}acetic    acid,-   (15)    2-{4-[N-(4,5-diphenylpyrimidin-2-yl)-N-methylamino]butyloxy}acetic    acid,-   (16)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(p-toluenesulfonyl)acetamide,-   (17)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(isopropylsulfonyl)acetamide,-   (18)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(trifluoromethanesulfonyl)acetamide,-   (19)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(o-toluenesulfonyl)acetamide,-   (20)    N-(benzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,-   (21)    N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,-   (22)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-methoxybenzenesulfonyl)acetamide,-   (23)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-fluorobenzenesulfonyl)acetamide,-   (24)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(2-thiophenesulfonyl)acetamide,-   (25)    N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,-   (26)    N-(N,N-dimethylaminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,-   (27)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(morpholin-4-ylsulfonyl)acetamide,-   (28)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(pyrrolidin-1-ylsulfonyl)acetamide,-   (29)    N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic    acid phenyl ester,-   (30)    N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic    acid,-   (31)    N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic    acid sodium salt, and-   (32)    2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.

The present invention will be described in detail below.

Examples of “alkyl” include a straight or branched alkyl having 1 to 6carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, andisohexyl. Particularly, alkyl having 1 to 4 carbon atoms is preferable.

Examples of the alkyl moiety of “haloalkyl”, “arylalkyl”, “alkylthio”,“alkoxyalkyl”, “alkylsulfonyl”, “monoalkylamino”, “dialkylamino”,“monoalkylcarbazoyl” and “dialkylcarbamoyl” include alkyl describedabove.

Examples of “alkoxy” include a straight or branched alkoxy having 1 to 6carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy,n-hexyloxy, and isohexyloxy. Particularly, alkoxy having 1 to 4 carbonatoms is preferable.

Examples of the alkyl moiety of “alkoxycarbonyl” and “alkoxyalkyl”include alkyl described above.

Examples of “alkenyl” include a straight or branched alkenyl having 2 to6 carbon atoms, for example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and5-hexenyl. Particularly, alkenyl having 3 to 4 carbon atoms ispreferable.

Examples of “cycloalkyl” include a cycloalkyl having 3 to 8 carbonatoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Particularly, cycloalkyl having 5 to 7carbon atoms is preferable.

Examples of “halogen” include fluorine, chlorine, bromine and iodineatoms.

Examples of “aryl” include a aryl having 6 to 10 carbon atoms, forexample, phenyl, 1-naphthyl, and 2-naphthyl. Particularly, phenyl ispreferable.

Examples of the aryl moiety of “arylalkyl” and “aryloxy” include aryldescribed above.

Examples of “alkylene” include a straight or branched alkylene having 1to 8 carbon atoms, for example, methylene, ethylene, 1-methylethylene,2-methylethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, and octamethylene. Particularly, alkylenehaving 3 to 6 carbon atoms is preferable, and alkylene having 4 carbonatoms is more preferable.

Examples of “alkenylene” include a straight or branched alkenylenehaving 2 to 8 carbon atoms, for example, ethenylene, 1-propenylene,2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene,2-pentenylene, 3-pentenylene, 4-pentenylene, 4-methyl-3-pentenylene,1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene,1-heptenylene, 2-heptenylene, 3-heptenylene, 4-heptenylene,5-heptenylene, 6-heptenylene, 1-octenylene, 2-octenylene, 3-octenylene,4-octenylene, 5-octenylene, 6-octenylene, and 7-octenylene.Particularly, alkenylene having 3 to 6 carbon atoms is preferable, andalkenylene having 4 carbon atoms is more preferable.

Examples of “heterocyclic group” include the following groups (1) to(2).

(1) Examples of the heterocyclic group include 5- to 6-membered aromaticring group having 1 to 4 hetero atoms selected from nitrogen, oxygen andsulfur atoms, or a benzene condensed ring thereof, and nitrogen andsulfur atoms may formed an oxide when a ring-constituent atom isnitrogen atom or sulfur atom. Examples thereof include 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 3-indolyl, 2-furanyl, 3-furanyl, 3-benzofuranyl,2-thienyl, 3-thienyl, 3-benzothienyl, 1,3-oxazol-2-yl, 4-isooxazolyl,2-thiazolyl, 5-thiazolyl, 2-benzothiazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 2-benzimidazolyl, 1H-1,2,4-triazol-1-yl, 1H-tetrazol-5-yl,2H-tetrazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyrazolyl,2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, and 1,3,5-triazin-2-yl.

(2) Examples of the heterocyclic group include 4- to 8-memberedsaturated ring group which optionally has 1 to 4 same or differentnitrogen, oxygen or sulfur atoms, or a benzene condensed ring thereof,and nitrogen and sulfur atoms may formed an oxide when aring-constituent atom is nitrogen atom or sulfur atom. Examples thereofinclude piperidino, piperazinyl, 3-methylpiperazin-1-yl,homopiperazinyl, morpholino, thio morpholino, 1-pyrrolidinyl,2-pyrrolidinyl, and 2-tetrahydrofuranyl.

The compounds of the present invention can be produced, for example, bythe method described below.

In the following method, in case the starting material has a substituentwhich would not like to be reacted (for example, hydroxy, amino, orcarboxy), the starting material is commonly used in the reaction afterpreviously being protected with a protective group (for example,methoxymethyl, 2-methoxyethoxymethyl, benzyl, 4-methoxybenzyl,triphenylmethyl, 4,4′-dimethoxytrityl, acetyl, tert-butoxycarbonyl,benzyloxycarbonyl, phthaloyl, tetrahydropyranyl, ortert-butyldimethylsilyl) by a known method. After the completion of thereaction, the protective group can be eliminated by a known method suchas catalytic reduction, alkali treatment, or acid treatment.

Method 1 (Preparation of a Heterocyclic Derivative (1a) wherein A isNR⁷, O, or S in the Heterocyclic Derivative (1))

wherein A¹ represents NR⁷, O, or S, L represents an eliminating groupsuch as halogen, mesyloxy, or tosyloxy, and Y, Z, R¹, R², R³, R⁴, D, E,G and Q are as defined in the general formula (1)

A heterocyclic derivative (1a) can be prepared by reacting a compound(4) with a compound (5). This reaction is usually carried out by usingexcess compound (5) or a base in the absence of a solvent or in a propersolvent. The amount of the compound (5) is from 1 to 20 moles, andpreferably from 1 to 10 moles, per mole of the compound (4). Examples ofthe base include organic amine (for example, pyridine, triethylamine,triethanolamine, N-methyldiethanolamine, N,N-diisopropylethanolamine, ortriisopropanolamine), metal hydride (for example, sodium hydride), andinorganic base (for example, potassium carbonate, sodium hydrogencarbonate, sodium hydroxide, or potassium hydroxide). The solvent is notspecifically limited as far as it does not take part in the reaction andexamples thereof include ethers such as tetrahydrofuran and diethylether; amides such as N,N-dimethylformamide and N,N-dimethylacetamide;nitrites such as acetonitrile and propionitrile; hydrocarbons such asbenzene and toluene; and mixed solvents thereof. The reactiontemperature varies depending on the kind of the starting material andbase to be used and reaction temperature, but is usually from 0° C. to300° C. The reaction time varies depending on the kind of the startingmaterial to be used and reaction temperature, but is preferably from 30minutes to 100 hours.

Method 2 (Separate Preparation of a Heterocyclic Derivative (1a))

wherein A¹ and L are as defined above, and Y, Z, R¹, R², R³, R⁴, D, E, Gand Q are as defined in the general formula (1)

A heterocyclic derivative (1a) can be prepared by reacting a compound(6) (also including a tautomer) with a compound (7). This reaction iscarried out in an organic solvent (for example, ethers such astetrahydrofuran and diethyl ether; amides such as N,N-dimethylformamideand N,N-dimethylacetamide; nitrites such as acetonitrile andpropionitrile; hydrocarbons such as benzene and toluene; and mixedsolvents thereof) in the presence of a base. The base to be used is thesame as that described in the method 1. The amount of the compound (7)is from 1 to 10 moles, and preferably from 1 to 2 moles, per mole of thecompound (6). The reaction temperature varies depending on the kind ofthe starting material and base to be used, but is usually from 0 to 150°C. The reaction time varies depending on the kind of the startingmaterial and base and the reaction temperature, but is preferably from30 minutes to 24 hours.

Method 3 (Preparation of a Heterocyclic Derivative (1b) wherein A isNR⁷, O, or S, and G is O in the Heterocyclic Derivative (1))

wherein A¹ and L are as defined above, and Y, Z, R¹, R², R³, R⁴, D, Eand Q are as defined in the general formula (1)Step 1

A compound (9) can be prepared by reacting a compound (4) with acompound (8). This reaction can be carried out in the same manner as inthe method 1.

Step 2

A heterocyclic derivative (1b) can be prepared by reacting a compound(9) with a compound (10). This reaction can be carried out according toa known method, for example, a method of B. P. Czech et al.(Tetrahedron, 41, 5439 (1985)), a method of A. Takahashi et al. (J. Org.Chem., 53, 1227 (1988)), or a method of N. A. Meanwell et al. (J. Med.Chem., 35, 3498 (1992)).

Method 4 (Separate Preparation of a Heterocyclic Derivative (1b) whereinA is NR⁷, O, or S, and G is O in the Heterocyclic Derivative (1))

wherein A¹ and L are as defined above, and Y, Z, R¹, R², R³, R⁴, D, Eand Q are as defined in the general formula (1)Step 1

A compound (9) can be prepared by reacting a compound (6) (alsoincluding a tautomer) with a compound (11). This reaction can be carriedout in the same manner as in the method 2.

Step 2

A heterocyclic derivative (1b) can be prepared by reacting a compound(9) with a compound (10) in the same manner as in the step 2 of themethod 3.

Method 5 (Preparation of Heterocyclic Derivative (1c) wherein E isSingle Bond, and G is O or S in the Heterocyclic Derivative (1))

wherein G¹ represents O or S, A and L are as defined above, and Y, Z,R¹, R², R³, R⁴, D and Q are as defined in the general formula (1)

A heterocyclic derivative (1c) can be prepared by reacting a compound(12) with a compound (13). This reaction is carried out by using a basein the absence of a solvent or in a proper solvent. The base to be usedis the same as that described in the method 1. The solvent to be used isnot specifically limited as far as it does not take part in the reactionand examples thereof include ethers such as tetrahydrofuran and diethylether; amides such as N,N-dimethylformamide and N,N-dimethylacetamide;nitrites such as acetonitrile and propionitrile; hydrocarbons such asbenzene and toluene; water; and mixed solvents thereof. When usingadditives, for example, phase transfer catalysts such ashexadecyltributyl phosphonium bromide and iodides such as sodium iodide,the reaction easily proceeds, sometimes. The reaction temperature variesdepending on the kind of the starting material to be used, but isusually from 0° C. to 100° C. The reaction time varies depending on thekind of the starting material to be used and the reaction temperature,but is preferably from 30 minutes to 24 hours.

Method 6 (Preparation of a Heterocyclic Derivative (1e) wherein G is SOor a Heterocyclic Derivative (1f) wherein G is SO₂ in the HeterocyclicDerivative (1))

wherein A, Y, Z, R¹, R², R³, R⁴, D, E and Q are as defined in thegeneral formula (1)

A heterocyclic derivative (1e) can be prepared by oxidizing theheterocyclic derivative (1d) [compound wherein G is S in theheterocyclic derivative (1)] obtained by any method described above orbelow. This reaction can be carried out in a proper solvent (it is notspecifically limited as far as it does not take part in the reaction andexamples thereof include amides such as N,N-dimethylformamide andN,N-dimethylacetamide; hydrocarbons such as benzene and toluene;halogenated hydrocarbons such as chloroform and dichloromethane;alcohols such as methanol and ethanol; organic acids such as acetic acidand trifluoroacetic acid; water; and mixed solvents thereof) at −20 to100° C. in the presence of an oxidizing agent (for example, hydrogenperoxide, peracetic acid, metaperiodate, m-chloroperoxybenzoic acid,halogen, or N-chlorosuccinimide). The reaction time varies depending onthe kind of the starting material and the oxidizing agent and thereaction temperature, but is preferably from 30 minutes to 24 hours. Theamount of the oxidizing agent is preferably from 1 to 10 moles per moleof the heterocyclic derivative (1d).

A heterocyclic derivative (1f) can be prepared by oxidizing theheterocyclic derivative (1d) or the heterocyclic derivative (1e). Thisreaction can be carried out in the same solvent as described above inthe presence of an oxidizing agent. Examples of the oxidizing agentinclude hydrogen peroxide, peracetic acid, potassium peroxysulfate,permaganates, and sodium perborate. The reaction temperature andreaction time are the same as those described above.

In case a mixture of the heterocyclic derivative (1e) and theheterocyclic derivative (1f) is obtained as a product, the heterocyclicderivative (1e) and the heterocyclic derivative (1f) can be respectivelyseparated and purified from the mixture by a conventional separation andpurification means, for example, extraction, concentration,neutralization, filtration, recrystallization, column chromatography, orthin layer chromatography.

Method 7 (Preparation of a Heterocyclic Derivative (1h) wherein A is SOor a Heterocyclic Derivative (1i) wherein A is SO₂ in the HeterocyclicDerivative

wherein Y, Z, R¹, R², R³, R⁴, D, E, G and Q are as defined in thegeneral formula (1)

A heterocyclic derivative (1h) can be prepared by oxidizing aheterocyclic derivative (1g) [compound wherein A is S in theheterocyclic derivative (1)] obtained by any method described above.This reaction can be carried out in the same manner as in thepreparation of the heterocyclic derivative (1e) from the heterocyclicderivative (1d) in the method 6.

The heterocyclic derivative (1i) can be prepared by oxidizing theheterocyclic derivative (1g) or the heterocyclic derivative (1h). Thisreaction can be carried out in the same manner as in the preparation ofthe heterocyclic derivative (1f) from the heterocyclic derivative (1d)or heterocyclic derivative (1e) in the method 6.

In case a mixture of the heterocyclic derivative (1h) and theheterocyclic derivative (1i) is obtained as a product, the heterocyclicderivative (1h) and the heterocyclic derivative (1i) can be respectivelyseparated and purified from the mixture by a conventional separation andpurification means, for example, extraction, concentration,neutralization, filtration, recrystallization, column chromatography, orthin layer chromatography.

Method 8 (Preparation of Heterocyclic Derivative (1j) wherein A isEthylene in the Heterocyclic Derivative (1))

wherein L¹ represents halogen, M represents —CH═CH— or —C≡C—, and Y, Z,R¹, R², R³, R⁴, D, E, G and Q are as defined in the general formula (1)Step 1

A compound (16) can be prepared by reacting a compound (14) with acompound (15). This reaction can be carried out in a proper solvent at20 to 150° C. in the presence of a catalyst. As the solvent, forexample, there can be used polar solvents such as acetonitrile andN,N-dimethylformamide; ether solvents such as diethyl ether,tetrahydrofuran, and dioxane; hydrocarbon solvents such as benzene andtoluene; basic solvents such as triethylamine and piperidine; and mixedsolvents thereof. As the catalyst, for example, there can be usedpalladium catalysts such as dichloro(triphenylphosphine)palladium andtetrakis(triphenylphosphine)palladium; and metal halides such as copperiodide and copper bromide. The reaction time varies depending on thestarting material, catalyst and reaction temperature, but is usuallyfrom 30 minutes to 48 hours. The amount of the compound (15) is from 1to 10 moles, and preferably from 1 to 3 moles, per mole of the compound(14).

Using a compound (14) and an alkynyl tin, alkenyl tin, alkynyl zinc oralkenyl zinc compound, a compound (16) can be prepared by a knownmethod. Examples of the method include a method of Y. Akita et al.(Chem. Pharm. Bull., 34, 1447 (1986), Heterocycles, 23, 2327 (1985)).

Step 2

A heterocyclic derivative (1j) can be prepared by catalytic reduction ofa compound (16). The compound (1j) can be prepared by reacting withhydrogen under normal pressure or predetermined pressure at 20 to 50° C.in a proper solvent in the presence of a catalyst. Examples of thecatalyst to be use include platinum catalyst and palladium catalyst. Aweight ratio of the catalyst to the compound (16) is preferably fromabout 10 to 50%. The solvent is not specifically limited as far as itdoes not taken part in the reaction and examples thereof include water,methanol, ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran,ethyl acetate, acetic acid, and a mixed solvent thereof.

Alternatively, the heterocyclic derivative (1j) can be prepared directlyfrom the compound (14) by a method of T. Watanabe et al. (Heterocycles,29, 123 (1989)).

Method 9 (Preparation of a Heterocyclic Derivative (1k) wherein A isEthylene and G is 0 in the Heterocyclic Derivative (1))

wherein L¹ represents halogen, M represents —CH═CH— or —C≡C—, and Y, Z,R¹, R², R³, R⁴, D, E, G and Q are as defined in the general formula (1)Step 1

A compound (18) can be prepared by reacting a compound (14) with acompound (17). This reaction can be carried out in the same manner as inthe step 1 of the method 8.

Step 2

A compound (19) can be prepared by catalytic reduction of a compound(18). This reaction can be carried out in the same manner as in the step2 of the method 8.

Step 3

A heterocyclic compound (1k) can be prepared by reacting a compound (19)with a compound (10). This reaction can be carried out in the samemanner as in the step 2 of the method 3.

Method 10 (Preparation of a Heterocyclic Derivative (1n) wherein Q isCarboxy in the Heterocyclic Derivative (1))

wherein R¹³ represents alkyl, and A, Y, Z, R¹, R², R³, R⁴, D, E and Gare as defined in the general formula (1)

A heterocyclic derivative (1n) can be prepared by hydrolyzing theheterocyclic derivative (1m) obtained by any method described above.This reaction is carried out in a proper solvent in the presence of anacid or a base. Examples of the acid to be used include inorganic acidssuch as hydrochloric acid and sulfuric acid and examples of the base tobe used include inorganic bases such as sodium hydroxide and potassiumhydroxide. Examples of the solvent to be used include alcohols such asmethanol and ethanol; ethers such as tetrahydrofuran and dioxane; water;and mixed solvents thereof. The reaction temperature varies depending onthe starting material and catalyst, but is usually from −10 to 100° C.The reaction time varies depending on the starting material, catalystand reaction temperature, but is usually from 30 minutes to 5 hours.

Method 11 (Preparation of a Heterocyclic Derivative (1p) wherein Q isCarbamoyl, Monoalkylcarbamoyl, Dialkylcarbamoyl, or a Group Representedby the Formula (22) in the Heterocyclic Derivative (1))

wherein R¹¹ and R¹² are the same or different and each representshydrogen, alkyl, aminosulfonyl, monoalkylaminosulfonyl,dialkylaminosulfonyl, optionally substituted alkylsulfonyl, optionallysubstituted arylsulfonyl, optionally substituted aryloxysulfonyl, oroptionally substituted heterocyclic sulfonyl, and A, Y, Z, R¹, R², R³,R⁴, D, E and G are as defined in the general formula (1)

A heterocyclic derivative (1p) can be prepared by reacting aheterocyclic derivative (1n) or a reactive derivative thereof with acompound (20). Examples of the reactive derivative of the heterocyclicderivative (1n) include those used commonly in the amidation, forexample, acid halide (acid chloride or acid bromide), mixed acidanhydride, imidazolide, and active amide. When using carboxylic acid ofthe heterocyclic derivative (1n), the reaction is carried out at −20 to100° C. using condensing agents (for example,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophophonate, and diphenylphophoryl azide) inthe presence or absence of a base (for example, organic base such astriethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine,or 1,8-diazabicyclo[5.4.0]undec-7-ene). The solvent to be used is notspecifically limited as far as it does not take part in the reaction andexamples thereof include ethers such as tetrahydrofuran and diethylether; amides such as N,N-dimethylformamide and N,N-dimethylacetamide;nitrites such as acetonitrile and propionitrile; hydrocarbons such asbenzene and toluene; halogenated hydrocarbons such as chloroform anddichloromethane; and mixed solvents thereof. In this case, additives(for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide) can also beadded. The reaction time varies depending on the kind of the condensingagent and the reaction temperature, but is preferably from 30 minutes to24 hours. The amount of the compound (20) and the condensing agent ispreferably from 1 to 3 moles per mole of the heterocyclic derivative(1n). When using acid halide as the reactive derivative of theheterocyclic derivative (1n), the reaction is carried out at −20 to 100°C. using the same base and solvent as those described above. Thereaction time varies depending on the kind of the acid halide and thereaction temperature, but is preferably from 30 minutes to 24 hours. Theamount of the compound (20) is preferably from 1 to 3 moles per mole ofthe acid halide.

Method 12 (Preparation of a Heterocyclic Derivative (1r) wherein Q is—CONHSO₃H in the Heterocyclic Derivative (1))

Step 1

A compound (1q) can be prepared by reacting a compound (1n) or areactive derivative thereof with ammonia. This reaction can be carriedout in the same manner as in the method 11.

Step 2

A compound (1r) can be prepared by using the compound (1q) obtained inthe step 1 according to a known method (Tetrahedron, 39, 2577 (1983),Tetrahedron, 56, 5667 (2000), J. Org. Chem., 50, 3462 (1985), J. Chem.Soc., Perkin Trans. I, 649 (1988)), for example, by dissolving2-picolione in a halogenated solvent, adding chlorosulfonic acid andadding a compound (1q). The reaction temperature and reaction time varydepending on the starting material, but the reaction is preferablycarried out at −50 to 100° C. for 30 minutes to 5 hours.

The compounds (4) to (20) used as the starting material in thesereactions are known compounds, or can be prepared according to a knownmethod, or by the method described in Reference Examples.

The compounds of the present invention can be separated and purifiedfrom the above reaction mixture by a conventional separation andpurification means, for example, extraction, concentration,neutralization, filtration, recrystallization, column chromatography, orthin layer chromatography.

The compounds of the present invention can be used as a medicine in theform of a free base or acid, but can also be used after forming into apharmaceutically acceptable salt by a known method. In case thecompounds of the present invention are basic, examples of “salt” includesalts of inorganic acids such as hydrochloric acid, sulfuric acid,nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid,and salts of organic acids such as acetic acid, tartaric acid, lacticacid, citric acid, fumaric acid, maleic acid, succinic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonicacid.

In case the compounds of the present invention are acidic, examples of“salt” include alkali metal salts such as sodium salt and potassiumsalt, and alkali earth metal salts such as calcium salt.

In the compounds of the present invention, geometrical isomers (Z formand E form) exist and these isomers and a mixture thereof are alsoincluded in the present invention.

In the compounds of the present invention, those having asymmetriccarbon also exist and these optical isomers and a racemic form thereofare also included in the present invention. The optical isomer can beprepared from the racemic form obtained as described above by opticallyresolving with an optically active acid (for example, tartaric acid,dibenzoyltartaric acid, mandelic acid, or 10-camphorsulfonic acid)utilizing its basicity, or using a previously prepared optically activecompound as the starting material.

The compounds of the present invention are excellent PGI₂ receptoragonists and exert platelet aggregation inhibitory effect, vasodilationeffect, bronchodilatation effect, lipid deposition inhibitory effect andleucocyte activation inhibitory effect as shown in Test Examplesdescribed below, and also have low toxicity. Therefore, the compounds ofthe present invention are useful as a preventive or therapeutic agentfor transient ischemic attack (TIA), diabetic neuropathy, diabeticgangrene, peripheral vascular disease (for example, arteriosclerosisobliterans, intermittent claudication, peripheral arterial embolism,vibration disease and Raynaud's disease), systemic lupus erythematosus,reocclusion or restenosis after percutaneous transluminal coronaryangioplasty (PTCA), arteriosclerosis, thrombosis (for example, acutecerebral thrombosis), diabetic nephropathy, hypertension, pulmonaryhypertension, ischemic diseases (for example, cerebral infarction andmyocardial infarction), angina pectoris (for example, stable angina andunstable angina), glomerulonephritis, diabetic nephropathy, allergy,bronchial asthma, ulcer, bedsore (decubitus), restenosis afterintervention of coronary artery such as atherectomy and indwelling ofstent, and thrombocytopia caused by dialysis. Also the compounds of thepresent invention are useful as an agent for acceleration of genetherapy or angiogenesis therapy such as autologous bone marrow celltransplantation.

When the compounds of the present invention are administered as amedicine, they can be administered to a mammal including human as theyare or in a mixture with a pharmaceutically acceptable non-toxic inertcarrier, for example, as a pharmaceutical composition containing thecompound at a level of 0.1% to 99.5%, preferably 0.5% to 90%.

As a carrier, one or more of auxiliary agents for formulations such assolid, semi-solid and liquid diluent, filler and other auxiliary agentsfor drug formulations may be used. It is desirable that a pharmaceuticalcomposition is administered as a unit dosage form. The pharmaceuticalcomposition can be administered into tissue, or intravenously, orally,topically (percutaneously) or rectally. It is a matter of course that adosage form suitable for any of the administration modes described aboveis employed. For example, oral administration is preferable.

While it is desirable that the dose may be adjusted depending on theconditions of the patients including the age and body weight, theadministration route, nature and degree of the disease as well as adaily dose as an active ingredient in an adult is usually 0.01 mg to1000 mg per adult, preferably 0.1 mg to 100 mg per adult.

In some cases, a lower dose may be sufficient or a higher dose may berequired. Usually, the dose is given once or several times as beingdivided into portions.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be described in more detail withreference to Production Examples of Reference Examples, Examples andTest Examples, but the present invention is not limited thereto.

REFERENCE EXAMPLE 1

4-(isopropylamino)-1-butanol

100.40 g of 4-amino-1-butanol was dissolved in a mixed solvent of 108 mlof acetone and 160 ml of ethanol and, after adding 2.1 g of platinum(IV) oxide, hydrogenation was carried out under the pressure of 2 to 3atms for 48 hours. A catalyst was removed by filtering the reactionsolution and the filtrated was concentrated to obtain 147.64 g of thedesired compound as a colorless oily substance.

REFERENCE EXAMPLE 2

4-(cyclopentylamino)-1-butanol

In the same manner as in Reference Example 1, except that cyclopentanonewas used in place of acetone, a pale yellow oily substance was prepared.

REFERENCE EXAMPLE 3

4-(cyclohexylamino)-1-butanol

In the same manner as in Reference Example 1, except that cyclohexanonewas used in place of acetone, a colorless crystal having a melting pointof 48 to 50° C. was prepared.

REFERENCE EXAMPLE 4

4-(aminomethyl)-1-butanol

Step 1

4-(formylamino)-1-butanol

10 g of 4-amino-1-butanol was dissolved in 100 ml of ethanol and 13.6 mlof ethyl formate was added. After the mixture was heated at reflux for18 hours, the solvent was evaporated under reduced pressure to obtain13.29 g of the desired compound as a pale yellow oily substance.

Step 2

4-(aminomethyl)-1-butanol

6.36 g of aluminum lithium hydride was suspended in 100 ml oftetrahydrofuran and a solution of 13.29 g of 4-(formylamino)-1-butanolin 50 ml of tetrahydrofuran was dropwise at the rate which enables slowreflux. After the mixture was refluxed for 1.5 hours, the reactionsolution was ice-cooled and 6.3 ml of water, 6.3 ml of an aqueous 15%sodium hydroxide solution and 18.9 ml of water were added dropwise inorder, followed by stirring for 30 minutes. The insoluble matter wasremoved by filtration and the solvent in the filtrate was evaporatedunder reduced pressure. The residue was distilled off under reducedpressure to obtain 6.73 g of he desired compound as a colorless oilysubstance. Boiling point: 84 to 85° C./16 mmHg.

REFERENCE EXAMPLE 5

(±)-3-(2-pyrrolidinyl)-1-propanol

Step 1

(±)-N-benzyloxycarbonyl-2-pyrrolidine carboxylic acid methyl ester

To a solution of 28.83 g of (±)-N-benzyloxycarbonyl-2-pyrrolidinecarboxylic acid in 180 ml of N,N-dimethylformamide, 23.23 g of potassiumhydrogen carbonate and 10.8 ml of methyl iodide were added. Afterstirring at room temperature for 15 hours, the reaction solution wasdiluted with water and then extracted twice with diethyl ether. Afterthe extract was washed with an aqueous 5% sodium hydrogen sulfitesolution and water and dried over anhydrous magnesium sulfate, thesolvent was evaporated under reduced pressure to obtain 26.52 g of thedesired compound as a yellowish oily substance.

Step 2

(±)-N-benzyloxycarbonyl-2-formylpyrrolidine

To a solution of 12.00 g of (±)-N-benzyloxycarbonyl-2-pyrrolidinecarboxylic acid methyl ester in 50 ml of dry dichloromethane, 50 ml ofdiisobutylaluminum hydride (1M toluene solution) was added dropwiseunder an argon atmosphere at −70° C. or lower, followed by stirring for2 hours. To the reaction solution, 230 ml of 1N hydrochloric acid wasadded dropwise, and then the mixture was heated to room temperature andextracted with diethyl ether. The extract was washed with water anddried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography to obtain 4.72 g of the desired compound as acolorless oily substance.

Step 3

(±)-3-(N-benzyloxycarbonylpyrrolidin-2-yl)acrylic Acid Ethyl Ester

376 mg of 60% sodium hydride was washed with hexane to remove an oilcomponent and suspended in 10 ml of anhydrous tetrahydrofuran, and thena solution of 2.11 g of diethyl ethoxycarbonylmethanephosphonate in 2 mlof anhydrous tetrahydrofuran was added dropwise at room temperature.After stirring for 10 minutes, a solution of 2.00 g of(±)-N-benzyloxycarbonyl-2-formylpyrrolidine in 5 ml of anhydroustetrahydrofuran was added dropwise over about 10 minutes, followed bystirring for additional 30 minutes. The reaction solution was pouredinto water, extracted with diethyl ether and dried over magnesiumsulfate, and then the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain 1.86g of the desired compound as a colorless oily substance.

Step 4

(±)-3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propen-1-ol

To a solution of 1.86 g of(±)-3-(N-benzyloxycarbonylpyrrolidin-2-yl)acrylic acid ethyl ester in 15ml of dry dichloromethane1, 12.9 ml of diisobutylaluminum hydride (1Mtoluene solution) was added dropwise under an argon atmosphere at −70°C. or lower, followed by stirring for one hour. To the reactionsolution, 60 ml of 1N hydrochloric acid was added dropwise, and then themixture was heated to room temperature and extracted with diethyl ether.The extract was washed with water and dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain 0.75g of the desired compound as a colorless oily substance.

Step 5

(±)-3-(2-pyrrolidinyl)-1-propanol

0.73 g of (±)-3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propen-1-ol wasdissolved in 7 ml of ethanol and, after adding 200 mg of 5%palladium-carbon, the mixture was heated to 35° C. and hydrogenated atatmospheric pressure for 8 hours. A catalyst was removed by filteringthe reaction solution and the filtrate was concentrated under reducedpressure to obtain 0.34 g of the desired compound as a pale yellow oilysubstance.

REFERENCE EXAMPLE 6

6-chloro-2,3-diphenylpyridine

Step 1

2,3-diphenylpyridin-1-oxide

1 g of 2,3-diphenylpyridine was dissolved in chloroform and 1.4 g of 70%m-chloroperoxybenzoic acid was added, followed by stirring at roomtemperature for 15 hours. After the reaction solution was washed with anaqueous 5% potassium carbonate solution and saturated brine, and driedover anhydrous magnesium sulfate, the solvent was evaporated underreduced pressure to obtain 1.3 g of a crude crystal. The crude crystalwas washed with diisopropyl ether to obtain 922 mg of the desiredcompound as a colorless crystal having a melting point of 167 to 170° C.

Step 2

6-chloro-2,3-diphenylpyridine

To 922 mg of 2,3-diphenylpyridin-1-oxide, 3 ml of phosphorus oxychloridewas added, followed by stirring at 100° C. for 15 minutes. The reactionsolution was poured into iced water, extracted with ethyl acetate andthen washed with an aqueous 5% potassium carbonate solution andsaturated brine. After drying over anhydrous magnesium sulfate, thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to obtain 428 mg of the desiredcompound as an oily substance.

REFERENCE EXAMPLE 7

(±)-1-(2-pyrrolidinyl)-4-(2-tetrahydropyranyloxy)butane

Step 1

(±)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-4-(2-tetrahydropyranyloxy)-1-butene

Under an argon atmosphere, a suspension of 6.76 g3-(2-tetrahydropyranyloxy)propyltriphenylphosphonium bromide in 30 ml ofdry tetrahydrofuran was ice-cooled and 8.7 ml of n-butyllithium (1.6Mhexane solution) was added dropwise. After stirring for 15 minutes, anice bath was removed and the mixture was continuously stirred for onehour. A solution of 2.70 g of(±)-N-benzyloxycarbonyl-2-formylpyrrolidine obtained in the Step 2 ofReference Example 5 in 15 ml of dry tetrahydrofuran was added dropwiseat room temperature, followed by stirring for 2 hours. The reactionsolution was ice-cooled and an aqueous saturated ammonium chloridesolution was added and, after extracting with diethyl ether, the extractwas washed with saturated brine and dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressured.The residue was purified by silica gel column chromatography to obtain3.40 g of the desired compound as a colorless oily substance.

Step 2

(±)-1-(2-pyrrolidinyl)-4-(2-tetrahydropyranyloxy)butane

3.40 g of(±)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-4-(2-tetrahydropyranyloxy)-1-butenewas dissolved in 30 ml of ethanol and 600 mg of 5% palladium-carbon wasadded. The mixture was heated to 35° C. to 40° C. and hydrogenated undernormal pressure for 24 hours. A catalyst was removed by filtering thereaction solution and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto obtain 1.42 g of a mixture of the desired compound and(±)-1-(2-pyrrolidinyl)-4-(2-tetrahydropyranyloxy)-1-butene as a paleyellow oily substance. To a solution of the resulting mixture in 14 mlof methanol, 200 mg of 5% palladium-carbon was added. The mixture washydrogenated under 2 atms at 30 to 40° C. for 2 hours. The abovepost-treatment and purification were carried out to obtain 1.43 g of thedesired compound as a pale yellow oily substance.

REFERENCE EXAMPLE 8

3-(methoxymethoxy)-N-methylbenzylamine

Step 1

3-(methoxymethoxy)benzaldehyde

A solution of 100 g of 3-hydroxybenzaldehyde and 214 ml ofN-ethyldiisopropylamine in 800 ml of dichloromethane was ice-cooled anda solution of 68.4 ml of chloromethyl methyl ether in 200 ml ofdichloromethane was added dropwise. After stirring for one hour, an icebath was removed and the mixture was continuously stirred at roomtemperature overnight. The reaction solution was washed in turn with anaqueous 10% sodium hydroxide solution and 10% citric acid and dried overmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was distilled off under reduced pressure to obtain81.3 g of the desired compound as a colorless oily substance. Boilingpoint: 125 to 127° C./10 mmHg

Step 2

3-(methoxymethoxy)-N-methylbenzylamine

5% platinum-carbon was suspended in 10 ml of methanol and a solution of3.00 g of 3-(methoxymethoxy)benzaldehyde in 10 ml of methanol and 2.1 mlof 40% methylamine (methanol solution) were added. After heating to 30°C. under 2 atm, hydrogen was added for 22 hours. A catalyst was removedby filtering the reaction solution and the filtrate was concentrated.The residue was purified by silica gel column chromatography to obtain2.51 g of the desired compound as a yellowish oily substance.

REFERENCE EXAMPLE 9

1-[3-(benzyloxy)phenyl]-2-(methylamino)ethane

Step 1

1-[3-(benzyloxy)phenyl]-2-(formylamino)ethane

To a solution of 8.60 g of 2-[3-(benzyloxy)phenyl]ethylamine in 50 ml ofethanol, 4.6 ml of ethyl formate was added and the mixture was heated atreflux for 18 hours. The solvent was evaporated under reduced pressureand the residue was purified by silica gel column chromatography toobtain 4.81 g of the desired compound as a pale orange oily substance.

Step 2

1-[3-(benzyloxy)phenyl]-2-(methylamino)ethane

1.07 g of aluminum lithium hydride was suspended in 20 ml oftetrahydrofuran and a solution of 4.78 g of1-[3-(benzyloxy)phenyl]-2-(formylamino)ethane in 10 ml oftetrahydrofuran was added dropwise at room temperature. The mixture wasstirred at room temperature for 30 minutes and then heated at reflux for2 hours. The reaction solution was ice-cooled and 1 ml of water, 1 ml ofan aqueous 15% sodium hydroxide solution and 3 ml of water were addeddropwise in order, followed by stirring for 30 minutes. The insolublesolid was removed by filtration and the solvent in the filtrate wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography to obtain 3.46 g of the desired compound as apale yellow oily substance.

REFERENCE EXAMPLE 10

1-methylamino-4-(methoxymethoxy)indane

Step 1

4-(methoxymethoxy)-1-indanone

To a solution of 4.12 g of 4-hydroxy-1-indanone and 7.3 ml ofN-ethyldiisopropylamine in 30 m of dichloromethane, 2.3 ml ofchloromethyl methyl ether was added dropwise while stirring under icecooling. An ice bath was removed and the mixture was continuouslystirred overnight. The reaction solution was diluted with diethyl ether,washed with water, an aqueous 10% citric acid solution and an aqueous 5%sodium hydroxide solution, and then dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure to obtain4.23 g of the desired compound as a pale orange crystal having a meltingpoint of 51 to 54° C.

Step 2

1-methylamino-4-(methoxymethoxy)indane

To a solution of 1.00 g of 4-(methoxymethoxy)-1-indanone in 10 ml ofethanol, 2.8 ml of 40% methylamine (methanol solution) and 367 mg ofsodium cyanoborohydride were added. While stirring at room temperature,0.55 ml of acetic acid was added dropwise and the mixture was heated atreflux for 4 hours. The reaction solution was air-cooled, combined withwater and then extracted with ethyl acetate. After drying over anhydrousmagnesium sulfate, the solvent was evaporated. The residue was purifiedby silica gel column chromatography to obtain 0.61 g of the desiredcompound as a deep green oily substance.

REFERENCE EXAMPLE 11

2-(4-bromobutyloxy)acetic acid tert-butyl ester

Step 1

4-(2-tetrahydropyranyloxy)-1-butanol

To a solution of 100.0 g of 1,4-butanediol and 20 ml of3,4-dihydro-2H-pyrane in 80 ml of dichloromethane and 140 ml oftetrahydrofuran, 1.8 g of pyridinium p-toluenesulfonate was added. Afterstirring at room temperature for 18 hours, the solvent was evaporatedunder reduced pressure. The residue was extracted three times withdiethyl ether after adding saturated brine. After the extract was washedwith a small amount of water and dried over anhydrous magnesium sulfate,the solvent was evaporated to obtain 35.98 g of the desired crudeproduct as a colorless oily substance.

Step 2

2-[4-(2-tetrahydropyranyloxy)butyloxy]acetic Acid Tert-Butyl Ester

35.98 g of 4-(2-tetrahydropyranyloxy)-1-butanol was dissolved in 300 mlof benzene and then 33.95 g of tetra-n-butylammonium hydrogen sulfateand 300 ml of an aqueous 40% potassium hydroxide solution were added.While stirring vigorously under ice cooling, 10.5 ml of tert-butylbromoacetate was added dropwise so as to control the inner temperatureto 5 to 10° C. or lower. After stirring for 45 minutes, an ice bath wasremoved and the mixture was stirred at room temperature for one hour.The reaction solution was diluted with water and then extracted withdiethyl ether. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and then the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography to obtain 36.21 g of the desired compound as a colorlessoily substance.

Step 3

2-(4-hydroxybutyloxy)acetic Acid Tert-Butyl Ester

To a solution of 36.21 g of 2-[4-(2-tetrahydropyranyloxy)butyloxy]aceticacid tert-butyl ester in 360 ml of methanol, 47.77 g ofp-toluenesulfonic acid monohydrate was added. After stirring at roomtemperature for 30 minutes, the reaction solution was neutralized withan aqueous sodium hydrogen carbonate solution and the solvent wasevaporated under reduced pressure. The residue was diluted with water,extracted with diethyl ether, washed with water and dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto obtain 17.02 g of the desired compound as a colorless oily substance.

Step 4

2-(4-bromobutyloxy)acetic Acid Tert-Butyl Ester

To a solution of 17.02 g of 2-(4-hydroxybutyloxy)acetic acid tert-butylester in 400 ml of dichloromethane, 24.04 g of triphenylphosphine and31.78 g of carbon tetrabromide were added. After stirring at roomtemperature for one hour, the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto obtain 16.95 g of the desired compound as a colorless oily substance.

REFERENCE EXAMPLE 12

5,6-diphenyl-2-(ethylamino)pyrazine

1.00 g of 2-chloro-5,6-diphenylpyrazine was added to 18.7 ml of 2Methylamine in methanol and the mixture was reacted in a sealed tube at80° C. for 16 hours. After cooling, 12 ml of a 2M ethylaminemethanolsolution was further added, followed by continuous stirring in thesealed tube at 90° C. for 17.5 hours and further stirring at roomtemperature for 46 hours. After the solvent was evaporated under reducedpressure, the residue was purified by silica gel column chromatographyto obtain 531 mg of the desired compound as a pale yellow crystal havinga melting point of 121 to 123° C.

REFERENCE EXAMPLE 13

2-allylamino-5,6-diphenylpyrazine

To a solution of 1.00 g of 2-chloro-5,6-diphenylpyrazine in 10 ml ofmethanol, 2.14 g of allylamine was added and the mixture was reacted ina sealed tube at 80° C. for 41 hours, followed by stirring at roomtemperature for 54 hours. After the solvent was evaporated under reducedpressure, the reaction solution was combined with water, extracted withchloroform, dried over anhydrous magnesium sulfate, and then the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography to obtain 330 mg of the desiredcompound as a pale yellow crystal having a melting point of 97 to 100°C.

REFERENCE EXAMPLE 14

2-[4-chloro-(Z)-2-buten-1-yloxy]acetic acid tert-butyl ester

Step 1

(Z)-4-(2-tetrahydropyranyloxy)-2-buten-1-ol

50 g of 1,4-butenediol was dissolved in 200 ml of tetrahydrofuran and280 mg of pyridinium p-toluenesulfonate was added and a solutionprepared by dissolving 10.27 g of 3,4-dihydro-2H-pyrane in 50 ml oftetrahydrofuran was added dropwise under ice cooling. After thetemperature was returned to room temperature, the reaction solution wasstirred for 21 hours. The solvent was evaporated under reduced pressureand the residue was extracted with diethyl ether after adding water. Theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure to obtain 7.05 g of a desired crude product as a colorless oilysubstance.

Step 2

2-[4-(2-tetrahydropyranyloxy)-(Z)-2-buten-1-yloxy]acetic Acid Tert-ButylEster

6.00 g of (Z)-4-(2-tetrahydropyranyloxy)-2-buten-1-ol was dissolved in10 ml of benzene and 1.18 g of tetra-n-butylammonium hydrogen sulfateand 10 ml of an aqueous 50% sodium hydroxide solution were added and6.75 ml of tert-butyl bromoacetate was added dropwise while stirringunder ice cooling. After 10 minutes, the temperature was returned toroom temperature and the reaction solution was stirred for one hour. Thesolution was extracted with diethyl ether after adding ice water. Theextract was washed with saturated brine and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography to obtain 1.00 g of the desired compound as a colorlessoily substance.

Step 3

2-[4-hydroxy-(Z)-2-buten-1-yloxy]acetic Acid Tert-Butyl Ester

To a solution of 1.00 g of2-[4-(2-tetrahydropyranyloxy)-(Z)-2-buten-1-yloxy]acetic acid tert-butylester in 30 ml of methanol, 88 mg of pyridinium p-toluenesulfonate wasadded and the mixture was heated at reflux for 3 hours. The solvent wasevaporated under reduced pressure and the reaction solution wasextracted with ethyl acetate after adding water. After the extract wasdried over anhydrous magnesium sulfate, the solvent was evaporated underreduced pressure to obtain 420 mg of the desired compound as an oilysubstance.

Step 4

2-[4-chloro-(Z)-2-buten-1-yloxy]acetic Acid Tert-Butyl Ester

To a solution of 420 mg of 2-[4-hydroxy-(Z)-2-buten-1-yloxy]acetic acidtert-butyl ester in 10 ml of N,N-dimethylformamide, 1.00 g of2,4,6-collidine and 350 mg of lithium chloride were added. Whilestirring under ice cooling, 0.64 ml of methanesulfonyl chloride wasadded dropwise, followed by stirring at room temperature for 2 hours.The reaction solution was extracted with ethyl acetate after adding icedwater, and dried over anhydrous magnesium sulfate, and then the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography to obtain 350 mg of the desiredcompound as a colorless oily substance.

REFERENCE EXAMPLE 15

2-[4-chloro-(E)-2-buten-1-yloxy]acetic acid methyl ester

Step 1

2-[3-formyl-(E)-2-propen-1-yloxy]acetic acid methyl ester

To a solution of 1.57 g of 2-[4-hydroxy-(Z)-2-buten-1-yloxy]acetic acidmethyl ester in 157 ml of benzene, 7.90 g of celite and 4.87 g ofpyridinium chlorochromate were added, followed by stirring at roomtemperature for 23 hours. The insoluble matter was removed by filtrationand the solvent in the filtrate was evaporated under reduced pressure.After the was dissolved in ethyl acetate, the insoluble matter wasremoved by filtering trough celite to obtain 311 mg of the desired crudeproduct as a brown oily substance.

Step 2

2-[4-hydroxy-(E)-2-buten-1-yloxy]acetic Acid Methyl Ester

To a solution of 311 mg of 2-[3-formyl-(E)-2-propen-1-yloxy]acetic acidmethyl ester in 10 ml of methanol, 149 mg of sodium borohydride wasadded, followed by stirring at room temperature for 4.5 hours. Thesolvent was evaporated under reduced pressure and the residue wasextracted with ethyl acetate after adding ice water. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate,and then the solvent was evaporated under reduced pressure to obtain 187mg of the desired crude product as an oily substance.

Step 3

2-[4-chloro-(E)-2-buten-1-yloxy]acetic Acid Methyl Ester

In the same manner as in the step 4 of Reference Example 14, except that2-[4-hydroxy-(E)-2-buten-1-yloxy]acetic acid methyl ester was used inplace of 2-[4-hydroxy-(Z)-2-buten-1-yloxy]acetic acid tert-butyl ester,the desired colorless oily substance was prepared.

REFERENCE EXAMPLE 16

2,3-diphenyl-5-(methylamino)pyrazine 1-oxide

To 1.00 g of 5-chloro-2,3-diphenylpyrazine 1-oxide, 20 ml of 40%methylamine in methanol was added and the mixture was-reacted in asealed tube at room temperature for 15 hours. The reaction solution wasextracted with ethyl acetate after adding water. The extract was driedover anhydrous magnesium sulfate and the solvent was evaporated underreduced pressure. The resulting crude crystal was washed withdiisopropyl ether to obtain 536 mg of the desired compound as a paleyellow crystal having a melting point of 145 to 147° C.

REFERENCE EXAMPLE 17

4,5-diphenyl-2-(methylamino)pyrimidine

Step 1

3-(dimethylamino)-1,2-diphenyl-2-propen-1-one

25.00 g of benzyl phenyl ketone was mixed with 92 ml ofN,N-dimethylformamide dimethyl acetal and then heated at reflux for onehour. Almost all of N,N-dimethylformamide dimethyl acetal was evaporatedunder reduced pressure and the deposited crystal was washed with diethylether. After drying, 31.40 g of the desired compound was obtained as apale yellow crystal having a melting point of 128 to 130° C.

Step 2

4,5-diphenyl-2-(methylamino)pyrimidine

10.00 g of 3-(dimethylamino)-1,2-diphenyl-2-propen-1-one, 6.90 g of1-methylguanidine hydrochloride and 8.70 g of potassium carbonate wereadded to 20 ml of xylene and then heated at reflux for 13 hours using areflux condenser equipped with a Dean-Stark water separator. Thereaction solution was extracted with ethyl acetate after adding water,dried over anhydrous magnesium sulfate, and then the solvent wasevaporated. The crude crystal was washed with diisopropyl ether anddried to obtain 6.51 g of the desired compound as a pale yellow crystalhaving a melting point of 136 to 138° C.

REFERENCE EXAMPLE 18

4,5-di-p-tolyl-2-(methylamino)pyrimidine

Step 1

N-methoxy-N-methyl-p-toluamide

To a solution of 10.00 g of p-toluoyl chloride in 300 ml ofdichloromethane, 6.94 g of N,O-dimethylhydroxyamine hydrochloride wasadded. The reaction solution was ice-cooled and 11.5 ml of pyridine wasadded dropwise. After the completion of dropwise addition, the mixturewas stirred at room temperature for one hour and the solvent wasevaporated under reduced pressure. The residue was combined with water,extracted with diethyl ether and then washed in turn with 10%hydrochloric acid, water and an aqueous saturated sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, thesolvent was evaporated under reduced pressure to obtain 10.40 g of thedesired compound as a colorless oily substance.

Step 2

1,2-di-p-tolylethan-1-one

Under an argon atmosphere, a solution of 10.40 g ofN-methoxy-N-methyl-p-toluamide in 100 ml of tetrahydrofuran wasice-cooled and 4-methylbenzylmagnesium chloride (solution prepared bydissolving 10.60 g of α-chloro-p-xylene and 1.94 g of magnesium in 85 mlof tetrahydrofuran) was added dropwise. After stirring for one hour, 100ml of 10% hydrochloric acid was slowly added. The reaction solution wasdiluted with water, extracted with diethyl ether, washed with water andthen dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the crude crystal was washed with diisopropylether and then dried under reduced pressure to obtain 8.43 g of thedesired compound as a colorless crystal having a melting point of 93 to100° C.

Step 3

4,5-di-p-tolyl-2-(methylamino)pyrimidine

In the same manner as in the Steps 1 and 2 of Reference Example 17,except that 1,2-di-p-tolylethan-1-one was used in place of benzyl phenylketone, the desired compound was obtained as a pale yellow crystalhaving a melting point of 160 to 162° C.

REFERENCE EXAMPLE 19

5-(benzyloxy)-2-(chloromethyl)-3,4-dihydronaphthalene

Step 1

5-(benzyloxy)-1-tetralone

To a solution of 4.86 g of 5-hydroxy-1-tetralone in 50 ml ofacetonitrile, 5.13 g of benzyl bromide and 6.22 g of potassium carbonatewere added and the mixture was heated at reflux for 4 hours. Theinsoluble matter was removed by filtration and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to obtain 6.62 g of the desired compound as a pale yellowoily substance.

Step 2

5-(benzyloxy)-2-(methoxycarbonyl)-1-tetralone

Under an argon atmosphere, 2.09 g of 60% sodium hydride was suspended in30 ml of anhydrous dioxane and 11.51 g of dimethyl carbonate was added.While stirring with heating in an oil bath at 80 to 85° C., a solutionof 6.58 g of 5-(benzyloxy)-1-tetralone in 15 ml of dioxane was addeddropwise over about one hour. After stirring for one hour, the reactionsolution was ice-cooled and 52 ml of an aqueous 1N acetic acid solutionwas added dropwise. The reaction solution was diluted with water,extracted with diethyl ether, washed with water and dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto obtain 7.95 g of the desired compound as a pale yellow oilysubstance.

Step 3

5-(benzyloxy)-1-hydroxy-2-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalene

A solution of 7.95 g of 5-(benzyloxy)-2-(methoxycarbonyl)-1-tetralone in80 ml of methanol was ice-cooled and 0.97 g of sodium borohydride wasadded in five portions. After stirring for 30 minutes, an ice bath wasremoved and the mixture was further stirred for 30 minutes. The reactionsolution was diluted with iced water, extracted with diethyl ether,washed with water and dried over anhydrous magnesium sulfate, and thenthe solvent was evaporated under reduced pressured. The residue waspurified by silica gel column chromatography to obtain 5.96 g of thedesired compound as a colorless oily substance.

Step 4

5-(benzyloxy)-2-(methoxycarbonyl)-3,4-dihydronaphthalene

To a solution of 5.96 g of5-(benzyloxy)-1-hydroxy-2-(methoxycarbonyl)-1,2,3,4-tetrahydronaphthalenein 23 ml of anhydrous pyridine, 4.37 g of p-toluenesulfonyl chloride wasadded. After stirring with heating at 70° C. for 3 hours, 0.72 g ofp-toluenesulfonyl chloride was further added, followed by stirring for1.5 hours. The reaction solution was extracted with diethyl ether afteradding iced water. The extract was washed in turn with water, 10%hydrochloric acid, water and an aqueous saturated sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate, thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to obtain 2.79 g of the desiredcompound as a colorless crystal having a melting point of 64 to 67° C.

Step 5

5-(benzyloxy)-2-(hydroxymethyl)-3,4-dihydronaphthalene

Under an argon atmosphere, to a solution of 2.79 g of5-(benzyloxy)-2-(methoxycarbonyl)-3,4-dihydronaphthalene in 30 ml of drydichloromethane, 24 ml of diisobutylaluminum hydride (1M toluenesolution) was added dropwise at −70° C. or lower, followed by stirringfor 20 minutes. To the reaction solution, 26 ml of an aqueous 10% sodiumhydroxide solution was added dropwise and, after heating to roomtemperature, the mixture was extracted with diethyl ether. The extractwas washed with saturated brine and dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain 2.25g of the desired compound as a colorless crystal having a melting pointof 59 to 61° C.

Step 6

5-(benzyloxy)-2-(chloromethyl)-3,4-dihydronaphthalene

Under an argon atmosphere, to a solution of 1.82 g of5-(benzyloxy)-2-(hydroxymethyl)-3,4-dihydronaphthalene and 0.55 g of4-(dimethylamino)pyridine in 30 ml of dichloromethane, 1.43 g ofp-toluenesulfonyl chloride was added. After 1.2 ml of triethylamine wasadded dropwise, the mixture was stirred at room temperature for 1.5hours. The reaction solution was poured into iced water and thenextracted with diethyl ether. The extract was washed in turn with 5%hydrochloric acid, water and an aqueous saturated sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate, and thenthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography to obtain 1.06 g of thedesired compound as a colorless oily substance.

REFERENCE EXAMPLE 20

1-bromo-4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butane

A solution of 1.50 g of4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol and 1.18 gof triphenylphosphine in 20 ml of dichloromethane was ice-cooled and1.49 g of carbon tetrabromide was added. After stirring for one hour,the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography to obtain 1.18 g of thedesired compound as a yellow oily substance.

REFERENCE EXAMPLE 21

5,6-bis(4-methoxyphenyl)-2-chloropyrazine

In the same manner as in the preparation of2-chloro-5,6-diphenylpyrazine described in the document (J. Am. Chem.Soc., 74, 1580 (1952)), the desired compound was prepared. Meltingpoint: 126 to 127° C.

In the same manner as in Reference Example 21, the following compoundswere prepared.

5,6-bis(4-fluorophenyl)-2-chloropyrazine (melting point: 91 to 92° C.)

2-chloro-5,6-di-p-tolylpyrazine (melting point: 112 to 117° C.)

REFERENCE EXAMPLE 22

Isopropylsulfonamide

While stirring under ice cooling, to a solution of saturated ammonia in40 ml of anhydrous tetrahydrofuran, 1.126 ml of isopropylsulfonylchloride was slowly added dropwise. After stirring under ice cooling for3 hours, the insoluble matter was removed by filtration and then thesolvent was evaporated under reduced pressure. To the resulting oilysubstance, diethyl ether was added and the deposited crystal wascollected by filtration and then dried under reduced pressure to obtain0.71 g of the desired compound as a yellowish crystal having a meltingpoint of 56 to 59° C.

REFERENCE EXAMPLE 23

4-methoxybenzenesulfonamide

In the same manner as in Reference Example 22, except that4-methoxybenzenesulfonyl chloride was used in place of isopropylsulfonylchloride, the desired compounds was obtained as a colorless crystalhaving a melting point of 110 to 112° C.

REFERENCE EXAMPLE 24

4-fluorobenzenesulfonamide

In the same manner as in Reference Example 22, except that4-fluorobenzenesulfonyl chloride was used in place of isopropylsulfonylchloride, the desired compound was obtained as a colorless crystalhaving a melting point of 123 to 125° C.

REFERENCE EXAMPLE 25

2-thiophenesulfonamide

In the same manner as in Reference Example 22, except that2-thiophenesulfonyl chloride was used in place of isopropylsulfonylchloride, the desired compound was obtained as a colorless crystalhaving a melting point of 144 to 145.5° C.

REFERENCE EXAMPLE 26

Morpholin-4-ylsulfonamide

5.00 g of sulfamide, 4.09 g of morpholine and 5 ml of 1,2-diethoxyethanewere mixed and heated with stirring in an oil bath at 120° C. for 11hours. The reaction solution was air-cooled to room temperature and thecrystal was washed with diethyl ether, washed with methanol and thendried under reduced pressure to obtain 5.98 g of the desired compound asan brownish crystal having a melting point of 158 to 161° C.

REFERENCE EXAMPLE 27

Pyrrolidin-1-ylsulfonamide

In the same manner as in Reference Example 26, except that pyrrolidinewas used in place of morpholine, the desired compound was obtained as abrownish crystal having a melting point of 94 to 97° C.

REFERENCE EXAMPLE 28

Sulfamic acid phenyl ester

To a solution of 4.98 g of phenol in 9 ml of toluene, a solution of 7.49g of chlorosulfonyl isocyanate in 5 ml of toluene was added dropwise atan inner temperature of 45° C. or lower. After the completion ofdropwise addition, the mixture was heated in an oil bath at 110° C. andcontinuously stirred for 12 hours. The reaction solution was ice-cooledand the insoluble matter was removed by filtration, and then thefiltrate was heated in an oil bath at 40° C. While stirring vigorously,1.2 ml of water was slowly added dropwise. The reaction solution wasice-cooled and the deposited crystal was collected by filtration, washedwith toluene and then dried under reduced pressure to obtain 6.46 g ofthe desired compound as a colorless crystal having a melting point of 78to 80° C.

EXAMPLE 1

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acidtert-butyl ester

Step 1

4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol

30 g of 2-chloro-5,6-diphenylpyrazine and 131.22 g of4-(isopropylamino)-1-butanol were mixed and then heated with stirring at190° C. for 10 hours. The reaction solution was air-cooled, poured intowater, extracted with diethyl ether, dried over anhydrous magnesiumsulfate and then concentrated. The residue was purified by silica gelcolumn chromatography to obtain 22.96 g of the desired compound as acolorless crystal having a melting point of 102 to 103° C.

Step 2

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic AcidTert-Butyl Ester

22.84 g of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanolwas dissolved in 160 ml of benzene and 10.73 g of tetra-n-butylammoniumhydrogen sulfate and 160 ml of an aqueous 40% potassium hydroxidesolution were added. While stirring vigorously under ice cooling, 10.73g of tert-butyl bromoacetate was added dropwise so as to control theinner temperature within a range from 5 to 10° C. After stirring for 45minutes, an ice bath was removed and the mixture was stirred at roomtemperature for one hour. The reaction solution was diluted with waterand then extracted with diethyl ether. The extract was washed with waterand dried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography to obtain 21.70 g of the desired compound as apale yellow oily substance.

¹H-NMR (CDCl₃)δ: 1.27 (6H,d), 1.48 (9H,s), 1.55 to 1.90 (4H,m), 3.45(2H,t), 3.58 (2H,t), 3.95 (2H,s), 4.82 (1H,qn), 7.17 to 7.50 (10H,m),8.00 (1H,s)

EXAMPLE 2

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-cyclopentylamino]butyloxy}aceticacid tert-butyl ester

In the same manner as in Example 1, except that4-(cyclopentylamino)-1-butanol was used in place of4-(isopropylamino)-1-butanol, the desired compound was prepared as apale yellow oily substance.

¹H-NMR (CDCl₃)δ: 1.48 (9H,s), 1.63 to 1.79 (10H,m), 1.98 to 2.00 (2H,m),3.48 (2H,t), 3.57 (2H,t), 3.95 (2H,s), 4.66 to 4.76 (1H,m), 7.20 to 7.48(10H,m), 8.02 (1H,s)

EXAMPLE 3

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-cyclohexylamino]butyloxy}aceticacid tert-butyl ester

In the same manner as in Example 1, except that4-(cyclohexylamino)-1-butanol was used in place of4-(isopropylamino)-1-butanol, the desired compound was prepared as ayellow oily substance.

¹H-NMR (CDCl₃)δ: 1.16 to 1.90 (14H,m), 1.48 (9H,s), 3.48 (2H,t), 3.57(2H,t), 3.95 (2H,s), 4.25 to 4.35 (1H,m), 7.21 to 7.49 (10H,m), 7.99(1H,s)

EXAMPLE 4

2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-isopropylamino]butyloxy}aceticacid tert-butyl ester

In the same manner as in Example 1, except that2-chloro-5,6-di-p-tolylpyrazine was used in place of2-chloro-5,6-diphenylpyrazine, the desired compound was prepared as ayellow oily substance.

¹H-NMR (CDCl₃)δ: 1.24 to 1.29 (6H,m), 1.48 (9H,s), 1.68 to 1.75 (4H,m),2.32 (3H,s), 2.33 (3H,s), 3.42 (2H,t), 3.57 (2H,t), 3.95 (2H,s), 4.79(1H,qn), 7.03 to 7.09 (4H,m), 7.24 to 7.29 (2H,m), 7.34 to 7.38 (2H,m),7.96 (1H,s)

EXAMPLE 5

2-{4-[N-(5,6-diphenylpyridin-2-yl)-N-methylamino]butyloxy}acetic acidtert-butyl ester

In the same manner as in Example 1, except that2-chloro-5,6-diphenylpyridine was used in place of2-chloro-5,6-diphenylpyrazine and 4-(methylamino)-1-butanol was used inplace of 4-(isopropylamino)-1-butanol, provided that the reactiontemperature of the step 1 was controlled within a range from 100 to 150°C., the desired compound was prepared as a pale brown oily product.

¹H-NMR (CDCl₃)δ: 1.47 (9H,s), 1.60 to 1.80 (4H,m), 3.12 (3H,s), 3.56(2H,t), 3.66 (2H,t), 3.92 (2H,s), 6.52 (1H,dd), 7.10 to 7.53 (11H,m)

EXAMPLE 6

2-{4-[N-(3-chloro-5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}aceticacid tert-butyl ester

In the same manner as in Example 1, except that2,3-dichloro-5,6-diphenylpyrazine was used in place of2-chloro-5,6-diphenylpyrazine, the desired compound was prepared as apale yellow oily substance.

¹H-NMR (CDCl₃)δ: 1.20 to 1.30 (6H,m), 1.40 to 1.50 (9H,m), 1.50 to 1.80(4H,m), 3.41 to 3.51 (4H,m), 3.89 (2H,s), 4.37 (1H,qn), 7.20 to 7.50(10H,m)

EXAMPLE 7

2-{4-[N-(5,6-di-p-tolyl-1,2,4-triazin-3-yl)-N-isopropylamino]butyloxy}aceticacid tert-butyl ester

In the same manner as in Example 1, except that3-chloro-5,6-di-p-tolyl-1,2,4-triazine was used in place of2-chloro-5,6-diphenylpyrazine, provided that the reaction temperature ofthe step 1 was controlled at 80° C. and the reaction time was controlledto 40 minutes, the desired compound was prepared as a yellowish brownoily substance.

¹H-NMR (CDCl₃)δ: 1.31 (6H,d), 1.48 (9H,s), 1.60 to 1.90 (4H,m), 2.35(6H,s), 3.50 to 3.70 (4H,m), 3.95 (2H,s), 5.10 (1H,m), 7.11 (4H,d), 7.40(4H,ddd)

EXAMPLE 8

2-{4-[N-(5,6-diphenyl-1,2,4-triazin-3-yl)-N-isopropylamino]butyloxy}aceticacid tert-butyl ester

In the same manner as in Example 1, except that3-chloro-5,6-diphenyl-1,2,4-triazine was used in place of2-chloro-5,6-diphenylpyrazine, provided that the reaction temperature ofthe step 1 was controlled to 80° C. and the reaction time was controlledto 30 minutes, the desired compound was prepared as a pale yellow oilysubstance.

¹H-NMR (CDCl₃)δ: 1.32 (6H,d), 1.47 (9H,s), 1.60 to 1.90 (4H,m),3.50 to3.70 (4H,m), 3.95 (2H,s), 5.11 (1H,m), 7.25 to 7.55 (10H,m)

2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acidtert-butyl ester

Step 1

4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]-1-butanol

To a solution of 3.00 g of 2-chloro-5,6-di-p-tolylpyrazine and 1.57 g of4-(methylamino)-1-butanol in 15 ml of N,N-dimethylformamide, 2.26 g ofpotassium carbonate was added. After heating with stirring at 100° C.for 26 hours, the reaction solution was extracted with diethyl etherafter adding ice water. The extract was washed in turn with water andsaturated brine and dried over anhydrous magnesium sulfate, and then thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography and the resulting crystal was washedwith diisopropyl ether to obtain 2.76 g of the desired compound as acolorless crystal having a melting point of 94 to 96° C.

Step 2

2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acidtert-butyl ester

In the same manner as in the step 2 of Example 1, except that4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]-1-butanol obtained inthe step 1 was used, the desired compound was prepared as a pale yellowoily substance. ¹H-NMR (CDCl₃)δ: 1.47 (9H,s), 1.59 to 1.90 (4H,m), 2.32(3H,s), 2.33 (3H,s), 3.16 (3H,s), 3.55 (2H,t), 3.66 (2H,t), 3.93 (2H,s),7.00 to 7.10 (4H,m), 7.20 to 7.40 (4H,m), 7.99 (1H,s)

EXAMPLE 10

2-[4-{N-[5,6-bis(4-methoxyphenyl)pyrazin-2-yl]-N-methylamino}butyloxy]aceticacid tert-butyl ester

In the same manner as in Example 9, except that5,6-bis(4-methoxyphenyl)-2-chloropyrazine was used in place of2-chloro-5,6-di-p-tolylpyrazine, the desired compound was prepared as apale yellow oily substance.

¹H-NMR (CDCl₃)δ: 1.47 (9H,s), 1.60 to 1.85 (4H,m), 3.16 (3H,s), 3.56(2H,t), 3.66 (2H,t), 3.80 (3H,s), 3.81 (3H,s), 3.94 (2H,s), 6.75 to 6.85(4H,m), 7.26 to 7.46 (4H,m), 7.96 (1H,s)

EXAMPLE 11

2-[4-{N-[5,6-bis(4-fluorophenyl)pyrazin-2-yl]-N-methylamino}butyloxy]aceticacid tert-butyl ester

In the same manner as in Example 9, except that5,6-bis(4-fluorophenyl)-2-chloropyrazine was used in place of2-chloro-5,6-di-p-tolylpyrazine, the desired compound was prepared as apale yellow oily substance.

¹H-NMR (CDCl₃)δ: 1.47 (9H,s), 1.61 to 1.90 (4H,m), 3.17 (3H,s), 3.56(2H,t), 3.67 (2H,t), 3.93 (2H,s), 6.91 to 7.03 (4H,m), 7.26 to 7.45(4H,m), 8.01 (1H,s)

EXAMPLE 12

2-{4-[N-(5,6-diphenyl-3-methylpyrazin-2-yl)-N-methylamino]butyloxy}aceticacid tert-butyl ester

In the same manner as in Example 9, except that2-chloro-5,6-diphenyl-3-methylpyrazine was used in place of2-chloro-5,6-di-p-tolylpyrazine, the desired compound was prepared as apale yellow crystal having a melting point of 48 to 51° C.

EXAMPLE 13

2-{2-[1-(5,6-diphenylpyrazin-2-yl)piperidine-4-yl]ethoxy}acetic acidtert-butyl ester

In the same manner as in Example 9, except that2-chloro-5,6-diphenylpyrazine was used in place of2-chloro-5,6-di-p-tolylpyrazine and 2-(piperidine-4-yl)ethanol was usedin place of 4-(methylamino)-1-butanol, the desired compound was preparedas a yellowish crystal having a melting point of 104 to 106° C.

EXAMPLE 14

(±)-2-{3-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]propyloxy}aceticacid tert-butyl ester

In the same manner as in Example 9, except that2-chloro-5,6-diphenylpyrazine was used in place of2-chloro-5,6-di-p-tolylpyrazine and (O)-3-(2-pyrrolidinyl)-1-propanolwas used in place of 4-(methylamino)-1-butanol, the desired compound wasprepared as pale yellow oily substance.

¹H-NMR (CDCl₃)δ: 1.47 (9H,s), 1.50 to 2.20 (8H,m), 3.40 to 3.75 (4H,m),3.93 (2H,s), 4.15 to 4.30 (1H,m), 7.20 to 7.50 (10H,m), 7.90 (1H,s)

EXAMPLE 15

2-{4-[N-(5,6-diphenyl-1,2,4-triazin-3-yl)-N-methylamino]butyloxy}aceticacid tert-butyl ester

In the same manner as in Example 9, except that3-chloro-5,6-diphenyl-1,2,4-triazine was used in place of2-chloro-5,6-di-p-tolylpyrazine, provided that the reaction temperatureof the step 1 was controlled to room temperature and the reaction timewas controlled to 3 hours, the desired compound was prepared-as a paleyellow oily substance.

¹H-NMR (CDCl₃)δ: 1.47 (9H,s), 1.60 to 1.90 (4H,m), 3.34 (3H,s), 3.57(2H,t), 3.86 (2H,t), 3.94 (2H,s), 7.25 to 7.55 (10H,m)

EXAMPLE 16

(±)-2-{4-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]butyloxy}aceticacid tert-butyl ester

Step 1

(±)-1-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]-4-(2-tetrahydropyranyloxy)butane

In the same manner as in the step 1 of Example 9, except that2-chloro-5,6-diphenylpyrazine was used in place of2-chloro-5,6-di-p-tolylpyrazine and(±)-1-(2-pyrrolidinyl)-4-(2-tetrahydropyranyloxy)butane was used inplace of 4-(methylamino)-1-butanol, the desired compound was prepared asa yellowish crystal having a melting point of 94 to 96° C.

Step 2

(±)-4-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]-1-butanol

To a solution of 1.25 g of(±)-1-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]-4-(2-tetrahydropyranyloxy)butanein 13 ml of methanol, 0.52 g of p-toluenesulfonic acid monohydrate wasadded, followed by stirring at room temperature for 3 hours. Thereaction solution was alkalified by adding an aqueous saturated sodiumhydrogen carbonate solution, and then extracted with ethyl acetate. Theextract was dried over anhydrous magnesium sulfate and the solvent wasevaporated under reduced pressure to obtain 1.10 g of the desiredcompound as a pale yellow oily substance.

Step 3

(±)-2-{4-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]butyloxy}aceticacid tert-butyl ester

In the same manner as in the step 2 of Example 1, except that(±)-4-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]-1-butanol was used,the desired compound was prepared as a pale yellow oily substance.

¹H-NMR (CDCl₃)δ: 1.30 to 2.20 (10H,m), 1.47 (9H,s), 3.42 to 3.75 (4H,m),3.92 (2H,s), 4.08 to 4.20 (1H,m), 7.20 to 7.50 (10H,m), 7.89 (1H,s)

EXAMPLE 17

(±)-2-{2-[1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl]ethoxy}acetic acidtert-butyl ester

Step 1

(±)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-1-(5,6-diphenylpyrazin-2-yl)piperidine

In the same manner as in the step 1 of Example 9, except that2-chloro-5,6-diphenylpyrazine was used in place of2-chloro-5,6-di-p-tolylpyrazine and(±)-3-[2-(tert-butyldimethylsilyloxy)ethyl]piperidine was used in placeof 4-(methylamino)-1-butanol, the desired compound was prepared.

Step 2

(±)-2-[1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl]ethanol

To a solution of 1.20 g of3-[2-(tert-butyldimethylsilyloxy)ethyl]-1-(5,6-diphenylpyrazin-2-yl)piperidinein 6 ml of tetrahydrofuran, 5.0 ml of 1M tetra-n-butylammonium fluoridein tetrahydrofuran was added. After stirring at room temperature for 2hours, the solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography to obtain 0.77 g of thedesired compound as a pale yellow amorphous.

Step 3

(±)-2-{2-[1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl]ethoxy}acetic acidtert-butyl ester

In the same manner as in the step 2 of Example 1, except that(±)-2-[1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl]ethanol was used, thedesired compound was prepared as a pale yellow oily substance.

¹H-NMR (CDCl₃)δ: 1.48 (9H,s), 1.53 to 1.99 (7H,m), 2.80 (1H,dd), 3.05(1H,td), 3.63 (2H,t), 3.96 (2H,s), 4.28 to 4.38 (2H,m), 7.21 to 7.48(10H,m), 8.17 (1H,s)

EXAMPLE 18

(R)-2-[3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-1-hydroxyethyl}phenoxy]aceticacid methyl ester

Step 1

(R)-3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-1-hydroxyethyl}phenol

In the same manner as in the step 1 of Example 9, except that2-chloro-5,6-diphenylpyrazine was used in place of2-chloro-5,6-di-p-tolylpyrazine and L-phenylephrine was used in place of4-(methylamino)-1-butanol, the desired compound was prepared as a palebrown amorphous.

Step 2

(R)-2-[3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-1-hydroxyethyl}phenoxy]aceticacid methyl ester

To a solution of 0.66 g of(R)-3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-1-hydroxyethyl}phenoland 0.28 g of methyl bromoacetate in 10 ml of acetonitrile, 2 mg ofpotassium iodide and 0.28 g of potassium carbonate were added and themixture was heated at reflux for 4 hours. The insoluble matter wasremoved by filtration and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto obtain 0.55 g of the desired compound as a pale orange amorphous.

¹H-NMR (CDCl₃)δ: 3.04 (3H,s), 3.75 to 4.01 (2H,m), 3.78 (3H,s), 4.63(2H,s), 5.02 to 5.17 (2H,m), 6.79 to 6.85 (1H,m), 7.00 to 7.05 (2H,m),7.20 to 7.50 (11H,m), 8.10 (1H,s)

EXAMPLE 19

2-[3-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}phenoxy]aceticacid methyl ester

Step 1

1-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-3-(methoxymethoxy)benzene

In the same manner as in the step 1 of Example 9, except that2-chloro-5,6-diphenylpyrazine was used in place of2-chloro-5,6-di-p-tolylpyrazine and3-(methoxymethoxy)-N-methylbenzylamine was used in place of4-(methylamino)-1-butanol, the desired compound was prepared as acolorless crystal having a melting point of 109 to 111° C.

Step 2

3-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}phenol

To a suspension of 0.91 g of1-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-3-(methoxymethoxy)benzenein 10 ml of methanol, 2 ml of a 18% hydrogen chloride-methanol solutionwas added. After stirring at room temperature for 2 hours, 1 ml of a 18%hydrogen chloride-methanol solution was further added and the mixturewas continuously stirred for one hour. After the solvent was evaporatedunder reduced pressure, the reaction solution was neutralized by addingan aqueous saturated sodium hydrogen carbonate solution and thenextracted with ethyl acetate. The crude crystal was washed with diethylether and then dried to obtain 0.66 g of the desired compound as acolorless crystal having a melting point of 156 to 157° C.

Step 3

2-[3-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}phenoxy]aceticacid methyl ester

In the same manner as in the step 2 of Example 18, except that3-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}phenol was used,the desired compound was prepared as colorless crystal having a meltingpoint of 132 to 134° C.

EXAMPLE 20

2-[3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethyl}phenoxy]aceticacid methyl ester

Step 1

1-(benzyloxy)-3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethyl}benzene

In the same manner as in the step 1 of Example 9, except that2-chloro-5,6-diphenylpyrazine was used in place of2-chloro-5,6-di-p-tolylpyrazine and1-[3-(benzyloxy)phenyl]-2-(methylamino)ethane was used in place of4-(methylamino)-1-butanol, the desired compound was prepared as a paleyellow crystal having a melting point of 78 to 78.5° C.

Step 2

3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethyl}phenol

To 1.17 g of1-(benzyloxy)-3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethyl}benzene,12 ml of ethanol and 6 ml of hydrochloric acid were added, followed byheating with stirring at 80° C. for 17 hours. The reaction solution wasair-cooled to room temperature, neutralized with an aqueous saturatedsodium hydrogen carbonate solution and then extracted with ethylacetate. The extract was washed with water, dried over anhydrousmagnesium sulfate, and then the solvent was evaporated under reducedpressure. The crude crystal was washed with diisopropyl ether and thendried to obtain 0.87 g of the desired compound as a pale yellow crystalhaving a melting point of 158 to 161° C.

Step 3

2-[3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethyl}phenoxy]aceticacid methyl ester

In the same manner as in the step 2 of Example 18, except that3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethyl}phenol was used,the desired compound was prepared as a pale yellow oily substance.

¹H-NMR (CDCl₃)δ: 2.94 (2H,t), 3.12 (3H,s), 3.79 (3H,s), 3.85 (2H,t),4.59 (2H,s), 6.70 to 6.91 (3H,m), 7.18 to 7.50 (11H,m), 8.02 (1H,s)

EXAMPLE 21

1-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-4-(methoxycarbonylmethoxy)indane

Step 1

1-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-4-(methoxymethoxy)indane

In the same manner as in the step 1 of Example 9, except that2-chloro-5,6-diphenylpyrazine was used in place of2-chloro-5,6-di-p-tolylpyrazine and1-methylamino-4-(methoxymethoxy)indane was use in place of4-(methylamino)-1-butanol, the desired compound was prepared as a paleyellow oily substance.

Step 2

1-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-4-hydroxyindane

220 mg of1-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-4-(methoxymethoxy)indanewas dissolved in 2 ml of a 25% hydrogen chloride-ethyl acetate solution,followed by stirring at room temperature for 3 hours. After addingwater, the reaction solution was neutralized with an aqueous saturatedsodium hydrogen carbonate solution and then extracted with ethylacetate. After drying over anhydrous magnesium sulfate, the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography to obtain 167 mg of the desired compound as apale yellow oily substance.

Step 3

1-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-4-(methoxycarbonylmethoxy)indane

In the same manner as in the step 2 of Example 18, except that1-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-4-hydroxyindane was used,the desired compound was prepared as a pale yellow oily substance.

EXAMPLE 22

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acidmethyl ester

Under an argon atmosphere, to a solution of 763 mg of5,6-diphenyl-2-(methylamino)pyrazine in 4 ml of N,N-dimethylformamide,140 mg of 60% sodium hydride was added, followed by stirring at 80° C.for 30 minutes. The reaction solution was ice-cooled and a solution of657 mg of 2-(4-bromobutyloxy)acetic acid methyl ester in 2 ml ofN,N-dimethylformamide was slowly added. After an ice bath was removed,the mixture was stirred at room temperature for 14 hours. The reactionsolution was combined with ice water and extracted with ethyl acetateand, after the extract was washed with saturated brine and dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto obtain 240 mg of the desired compound as a pale yellow oilysubstance.

¹H-NMR (CDCl₃)δ: 1.65 to 1.85 (4H,m), 3.18 (3H,s), 3.58 (2H,t), 3.68(2H,t), 3.75 (3H,s), 4.06 (2H,s), 7.20 to 7.50 (10H,m), 8.03 (1H,s)

EXAMPLE 23

7-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]heptanoic acid ethyl ester

In the same manner as in Example 22, except that ethyl 7-bromoheptanoicacid ethyl ester was used in place of 2-(4-bromobutyloxy)acetic acidmethyl ester, the desired compound was prepared as a pale yellow oilysubstance.

¹H-NMR (CDCl₃)δ: 1.25 (3H,t), 1.30 to 1.80 (8H,m), 2.28 (2H,t), 3.17(3H,s), 3.61 (2H,t), 4.12 (2H,q), 7.20 to 7.50 (10H,m), 8.02 (1H,s)

EXAMPLE 24

8-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]octanoic acid methyl ester

In the same manner as in Example 22, except that 8-bromooctanoic acidmethyl ester was used in place of 2-(4-bromobutyloxy)acetic acid methylester, the desired compound was prepared as a pale yellow oilysubstance.

¹H-NMR (CDCl₃)δ: 1.20 to 1.40 (5H,m), 1.50 to 1.75 (5H,m), 2.29 (2H,t),3.17 (3H,s), 3.60 (2H,t), 3.66 (3H,s), 7.20 to 7.50 (10H,m), 8.01 (1H,s)

EXAMPLE 25

9-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]nonanoic acid methyl ester

In the same manner as in Example 22, except that 9-bromononanoic acidmethyl ester was used in place of 2-(4-bromobutyloxy)acetic acid methylester, the desired compound was prepared as a pale yellow oilysubstance.

¹H-NMR (CDCl₃)δ: 1.20 to 1.40 (8H,m), 1.50 to 1.75 (4H,m), 2.29 (2H,t),3.17 (3H,s), 3.60 (2H,t), 3.66 (3H,s), 7.20 to 7.50 (10H,m), 8.01 (1H,s)

EXAMPLE 26

6-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]hexanoic acid ethyl ester

In the same manner as in Example 22, except that 6-bromohexanoic acidethyl ester was used in place of 2-(4-bromobutyloxy)acetic acid methylester, the desired compound was prepared as a pale yellow oilysubstance.

¹H-NMR (CDCl₃)δ: 1.24 (3H,t), 1.30 to 1.50 (2H,m), 1.60 to 1.80 (4H,m),2.30 (2H,t), 3.16 (3H,s), 3.62 (2H,t), 4.12 (2H,q), 7.20 to 7.50(10H,m), 8.01 (1H,s)

EXAMPLE 27

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-ethylamino]butyloxy}acetic acidtert-butyl ester

In the same manner as in Example 22, except that5,6-diphenyl-2-(ethylamino)pyrazine was used in place of5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acidtert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acidmethyl ester, the desired compound was prepared as a pale yellow oilysubstance.

¹H-NMR (CDCl₃)δ: 1.25 (3H,t), 1.47 (9H,s), 1.60 to 1.85 (4H,m), 3.55 to3.70 (6H,m), 3.93 (2H,s), 7.20 to 7.50 (10H,m), 8.00 (1H,s)

EXAMPLE 28

2-{4-[N-allyl-N-(5,6-diphenylpyrazin-2-yl)amino]butyloxy}acetic acidtert-butyl ester

In the same manner as in Example 22, except that2-allylamino-5,6-diphenylpyrazine was used in place of5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acidtert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acidmethyl ester, the desired compound was prepared as a pale yellow oilysubstance.

¹H-NMR (CDCl₃)δ: 1.47 (9H,s), 1.60 to 1.85 (4H,m), 3.55 to 3.70 (4H,m),3.93 (2H,s), 4.05 to 4.25 (2H,m), 5.15 to 5.30 (2H,m), 5.80 to 6.15(1H,m), 7.2 to 7.50 (10H,m), 7.99 (1H,s)

EXAMPLE 29

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(Z)-2-buten-1-yloxy}aceticacid tert-butyl ester

In the same manner as in Example 22, except that2-[4-chloro-(Z)-2-buten-1-yloxy]acetic acid tert-butyl ester was used inplace of 2-(4-bromobutyloxy)acetic acid methyl ester, the desiredcompound was prepared as a brown oily product.

¹H-NMR (CDCl₃)δ: 1.48 (9H,s), 3.16 (3H,s), 3.92 (2H,s), 4.24 (2H,d),4.37 (2H,d), 5.60 to 5.90 (2H,m), 7.20 to 7.50 (10H,m), 8.05 (1H,s)

EXAMPLE 30

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(E)-2-buten-1-yloxy}aceticacid methyl ester

In the same manner as in Example 22, except that2-[4-chloro-(E)-2-buten-1-yloxy]acetic acid methyl ester was used inplace of 2-(4-bromobutyloxy)acetic acid methyl ester, the desiredcompound was prepared as a pale yellow oily substance.

EXAMPLE 31

2,3-diphenyl-5-{N-[4-(tert-butoxycarbonylmethoxy)butyl]-N-methylamino}pyrazine1-oxide

In the same manner as in Example 22, except that2,3-diphenyl-5-(methylamino)pyrazine 1-oxide was used in place of5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acidtert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acidmethyl ester, the desired compound was prepared as a pale yellow oilysubstance.

¹H-NMR (CDCl₃)δ: 1.48 (9H,s), 1.60 to 1.80 (4H,m), 3.11 (3H,s), 3.50 to3.65 (4H,m), 3.94 (2H,s), 7.15 to 7.40 (10H,m), 7.75 (1H,s)

EXAMPLE 32

2-{4-[N-(4,5-diphenylpyrimidin-2-yl)-N-methylamino]butyloxy}acetic acidtert-butyl ester

In the same manner as in Example 22, except that4,5-diphenyl-2-(methylamino)pyrimidine was used in place of5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acidtert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acidmethyl ester, the desired compound was prepared as a pale yellow oilysubstance.

¹H-NMR (CDCl₃)δ: 1.47 (9H,s), 1.60 to 1.90 (4H,m), 3.24 (3H,s), 3.57(2H,t), 3.77 (2H,t), 3.93 (2H,s), 7.10 to 7.45 (10H,m), 8.33 (1H,s)

EXAMPLE 33

2-{4-[N-(4,5-di-p-tolylpyrimidin-2-yl)-N-methylamino]butyloxy}aceticacid tert-butyl ester

In the same manner as in Example 22, except that4,5-di-p-tolyl-2-(methylamino)pyrimidine was used in place of5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acidtert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acidmethyl ester, the desired compound was prepared as a pale yellow oilysubstance.

¹H-NMR (CDCl₃)δ: 1.47 (9H,s), 1.60 to 1.90 (4H,m), 2.32 (3H,s), 2.34(3H,s), 3.23 (3H,s), 3.56 (2H,t), 3.72 (2H,t), 3.93 (2H,s), 6.99 to 7.11(6H,m), 7.34 (2H,d), 8.28 (1H,s)

EXAMPLE 34

2-{4-[(5,6-diphenylpyrazin-2-yl)thio]butyloxy}acetic acid tert-butylester

To a solution of 500 mg of 5,6-diphenyl-2-pyrazinethiol in 20 ml ofacetone, 321 mg of sodium carbonate was added and a solution of 556 mgof 2-(4-bromobutyloxy)acetic acid tert-butyl ester in 2 ml of acetonewas added dropwise while stirring under ice-cooling, followed bystirring at room temperature for 24 hours. The solvent was evaporatedunder reduced pressure, and then the residue was combined with water andextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and then the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography to obtain 701 mg of the desiredcompound as a pale yellow oily substance.

¹H-NMR (CDCl₃)δ: 1.47 (9H,s), 1.70 to 2.00 (4H,m), 3.31 (2H,t), 3.55(2H,t), 3.92 (2H,s), 7.20 to 7.50 (10H,m), 8.44 (1H,s)

EXAMPLE 35

5-(tert-butoxycarbonylmethoxy)-2-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-1,2,3,4-tetrahydronaphthalene

Step 1

5-(benzyloxy)-2-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-3,4-dihydronaphthalene

Under an argon atmospshere, 0.97 g of 60% sodium hydride was suspendedin anhydrous N,N-dimethylformamide and 0.97 g of5,6-diphenyl-2-(methylamino)-pyrazine was added in three portions. Afterstirring at 80° C. for 30 minutes, the reaction solution was ice-cooledand a solution of 0.97 g of5-(benzyloxy)-2-(chloromethyl)-3,4-dihydronaphthalene in 5 ml ofanhydrous N,N-dimethylformamide was added dropwise. After stirring for30 minutes, the reaction solution was diluted with ice water and thenextracted with diethyl ether. The extract was washed with water anddried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography to obtain 1.81 g of the desired compound as apale yellow amorphous.

Step 2

2-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-5-hydroxy-1,2,3,4-tetrahydronaphthalene

To 800 mg of5-(benzyloxy)-2-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-3,4-dihydronaphthalene,18 ml of ethanol, 15 ml of ethyl acetate and 80 mg of 10%palladium-carbon were added and, after the mixture was hydrogenatedunder 3 atm at room temperature for 31 hours, the reaction was continuedat 30° C. for 23 hours. The catalyst was removed by filtration and thefiltrate was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to obtain 443 mg of the desiredcompound as a pale yellow oily substance.

Step 3

5-(tert-butoxycarbonylmethoxy)-2-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-1,2,3,4-tetrahydronaphthalene

To a solution of 413 mg of2-[N-(5,6-diphenylpyrazin-2-yl)-N-methyl(aminomethyl)]-5-hydroxy-1,2,3,4-tetrahydronaphthaleneand 210 mg of tert-butyl bromoacetate in 10 ml of acetonitrile, acatalytic amount of potassium iodide and 163 mg of potassium carbonatewere added and the mixture was heated at reflux for 4 hours. Theinsoluble matter was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to obtain 423 mg of the desired compound as apale orange oily substance.

¹H-NMR (CDCl₃)δ: 1.40 to 1.60 (1H,m), 1.48 (9H,s), 1.95 to 3.15 (6H,m),3.24 (3H,s), 3.53 to 3.80 (2H,m), 4.51 (2H,s), 6.52 (1H,d), 6.72 (1H,d),7.04 (1H,t), 7.10 to 7.50 (10H,m), 8.06 (1H,s)

EXAMPLE 36

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio}aceticacid methyl ester

1.17 g of1-bromo-4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butane, 0.29 gof methyl thioglycolate, 0.46 g of potassium carbonate, a catalyticamount of potassium iodide and 27 ml of acetonitrile were mixed and themixture was refluxed for 4 hours. The insoluble matter was removed byfiltration and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain 1.19g of the desired compound as a pale yellow crystal having a meltingpoint of 64 to 67° C.

EXAMPLE 37

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfinyl]aceticacid methyl ester

A solution of 600 mg of2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio}aceticacid methyl ester obtained in Example 36 in 10 ml of dichloromethane wasice-cooled and 329 mg of 70% m-chloroperoxybenzoic acid was added. Afterstirring under ice cooling for 2 hours, the reaction solution wasdiluted with an aqueous saturated sodium hydrogen carbonate solution andthen extracted with ethyl acetate. The extract was washed with water anddried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography to obtain 385 mg of the desired compound as ayellowish crystal having a melting point of 128 to 130° C.

EXAMPLE 38

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfonyl}aceticacid methyl ester

According to silica gel column chromatography in Example 37, 163 mg ofthe desired compound was obtained as a pale yellow crystal having amelting point of 123 to 125° C.

EXAMPLE 39

2-[4-(5,6-diphenylpyrazin-2-sulfinyl)butyloxy]acetic acid tert-butylester

While stirring under ice cooling, to a solution of 350 mg of2-{4-[(5,6-diphenylpyrazin-2-yl)thio]butyloxy}acetic acid tert-butylester obtained in Example 34 in 5 ml of chloroform, 191 mg of 70%m-chloroperoxybenzoic acid was added, followed by stirring for 2 hours.The reaction solution was combined with 20 ml of a 0.2N sodium hydroxidesolution, extracted with chloroform and dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography to obtain 145mg of the desired compound as a pale yellow oily substance.

¹H-NMR (CDCl₃)δ: 1.46 (9H,s), 1.70 to 2.20 (4H,m), 3.05 to 3.40 (2H,m),3.55 (2H,dd), 3.92 (2H,s), 7.20 to 7.55 (10H,m), 9.16 (1H,s)

EXAMPLE 40

2-[4-(5,6-diphenylpyrazin-2-sulfonyl)butyloxy]acetic acid tert-butylester

To a solution of 350 mg of2-{4-[(5,6-diphenylpyrazin-2-yl)thio]butyloxy]acetic acid tert-butylester obtained in Example 34 in 5 ml of chloroform, 421 mg of 70%m-chloroperoxybenzoic acid was added, followed by stirring at roomtemperature for 19 hours. The reaction solution was combined with 20 mlof 0.2N sodium hydroxide solution, extracted with chloroform and driedover anhydrous magnesium sulfate, and then the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography to obtain 380 mg of the desired compound as a colorlesscrystal having a melting point of 88 to 90° C.

EXAMPLE 41

2-[5-(5,6-diphenylpyrazin-2-yl)pentyloxy]acetic acid tert-butyl ester

Step 1

5,6-diphenyl-2-[5-(2-tetrahydropyranyloxy)-1-pentyn-1-yl]pyrazine

To a solution of 1.58 g of 2-chloro-5,6-diphenylpyrazine in 10 ml oftriethylamine, 1.20 g of 5-(2-tetrahydropyranyloxy)-1-pentyne, 208 mg ofdichlorobis(triphenylphosphine)palladium (II) and 56 mg of copper (I)iodide were added, followed by stirring under an argon atmosphere at 80°C. for 8 hours. The solvent was evaporated under reduced pressure andthe residue was dissolved in diethyl ether, and then the insolublematter was removed by filtration through celite. After the solvent wasevaporated under reduced pressure, the residue was purified by silicagel column chromatography to obtain 1.79 g of the desired compound as abrown oily substance.

Step 2

5,6-diphenyl-2-(5-hydroxy-1-pentyn-1-yl)pyrazine

To a solution of 1.79 g of5,6-diphenyl-2-[5-(2-tetrahydropyranyloxy)-1-pentyn-1-yl]pyrazine inmethanol, 1.13 g of pyridinium p-toluenesulfonate was added and themixture was heated at reflux for 30 minutes. The reaction solution waspoured into ice water while stirring, extracted with ethyl acetate andthen dried over anhydrous magnesium sulfate. After the solvent wasevaporated under reduced pressure, the resulting crystal wasrecrystallized from diisopropyl ether to obtain 1.00 g of the desiredcompound as a yellow crystal having a melting point of 88 to 90° C.

Step 3

5,6-diphenyl-2-(5-hydroxypentan-1-yl)pyrazine

To a solution of 400 mg of5,6-diphenyl-2-(5-hydroxy-1-pentyn-1-yl)pyrazine in 20 ml of ethanol, 80mg of 5% palladium-carbon was added and the mixture was hydrogenated at30° C. for 5 hours. After 40 mg of 5% palladium-carbon was furtheradded, hydrogenation was continued for one hour. The catalyst wasremoved by filtering the reaction solution through celite and thefiltrate was dried over anhydrous magnesium sulfate, and then thesolvent was evaporated under reduced pressure to obtain 398 mg of thedesired compound as a yellow oily substance.

Step 4

2-[5-(5,6-diphenylpyrazin-2-yl)pentyloxy]acetic acid tert-butyl ester

In the same manner as in the step 2 of Example 1, except that5,6-diphenyl-2-(5-hydroxypentan-1-yl)pyrazine was used in place of4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol, the desiredcompound was prepared as a pale yellow oily substance.

¹H-NMR (CDCl₃)δ: 1.40 to 2.00 (6H,m), 1.48 (9H,s), 2.92 (2H,t), 3.54(2H,t), 3.95 (2H,s), 7.20 to 7.50 (10H,m), 8.46 (1H,s)

EXAMPLE 42

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid

21.07 g of2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acidtert-butyl ester was dissolved in 200 ml of methanol and 60 ml of 1Nsodium hydroxide solution was added. After the mixture was heated atreflux for 2 hours, the solvent was evaporated under reduced pressureand the residue was dissolved in water. After washing with diethylether, the aqueous layer was neutralized with 60 ml of 1N hydrochloricacid and then extracted with ethyl acetate. The extract was dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure, and then the residue was washed with diisopropyl ether toobtain 15.82 g of the desired compound.

Elemental analysis (for C₂₅H₂₉N₃O₃) Calcd. (%): C, 71.58; H, 6.97; N,10.02. Found (%): C, 71.66; H, 7.03; N, 9.92.

EXAMPLE 43

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-cyclopentylamino]butyloxy}aceticacid

In the same manner as in Example 42, except that2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-cyclopentylamino]butyloxy}aceticacid tert-butyl ester was used, the desired compound was prepared as apale yellow crystal having a melting point of 101 to 103° C.

Elemental analysis (for C₂₇H₃₁N₃O₃) Calcd. (%): C, 72.78; H, 7.01; N,9.43. Found (%): C, 72.20; H, 7.26; N, 9.17.

EXAMPLE 44

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-cyclohexylamino]butyloxy}aceticacid

In the same manner as in Example 42, except that2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-cyclohexylamino]butyloxy}aceticacid tert-butyl ester was used, the desired compound was prepared as apale yellow crystal having a melting point of 130 to 131° C.

Elemental analysis (for C₂₈H₃₃N₃O₃) Calcd. (%): C, 73.18; H, 7.24; N,9.14. Found (%): C, 73.03; H, 7.34; N, 8.97.

EXAMPLE 45

2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-isopropylamino]butyloxy}aceticacid

In the same manner as in Example 42, except that2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-isopropylamino]butyloxy}aceticacid tert-butyl ester was used, the desired compound was prepared as apale yellow crystal having a melting point of 155 to 156° C.

Elemental analysis (for C₂₇H₃₃N₃O₃) Calcd. (%): C, 72.62; H, 7.22; N,9.41. Found (%): C, 72.61; H, 7.55; N, 9.12.

EXAMPLE 46

2-{4-[N-(5,6-diphenylpyridin-2-yl)-N-methylamino]butyloxy}acetic acidsodium salt

After 2-{4-[N-(5,6-diphenylpyridin-2-yl)-N-methylamino]butyloxy}aceticacid tert-butyl ester was hydrolyzed in the same manner as in Example42, the resulting2-{4-[N-(5,6-diphenylpyridin-2-yl)-N-methylamino]butyloxy}acetic acidwas treated with the same amount of 1N sodium hydroxide solution toobtain the desired compound as a pale brown amorphous.

Elemental analysis (for C₂₄H₂₅N₂O₃Na.0.4H₂O) Calcd. (%): C, 68.69; H,6.20; N, 6.68. Found (%): C, 68.69; H, 6.36; N, 6.36.

EXAMPLE 47

2-{4-[N-(3-chloro-5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}aceticacid

218 mg of2-{4-[N-(3-chloro-5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}aceticacid tert-butyl ester was dissolved in 2 ml of 1,4-dioxane and 2 ml of1N hydrochloric acid was added, followed by stirring at 80° C. for onehour. The mixture was further stirred at 110° C. for 4 hours. Thereaction solution was neutralized with 1N sodium hydroxide solution andthen extracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and then the solvent was evaporated under reducedpressure. The resulting crude crystal was washed with a solvent ofhexane-ethyl acetate (4:1) to obtain 120 mg of the desired product as agray crystal having a melting point of 136 to 138° C.

Elemental analysis (for C₂₅H₂₈ClN₃O₃) Calcd. (%): C, 66.14; H, 6.22; N,9.26. Found (%): C, 66.10; H, 6.32; N, 9.05.

EXAMPLE 48

2-{4-[N-(5,6-di-p-tolyl-1,2,4-triazin-3-yl)-N-isopropylamino]butyloxy}aceticacid

In the same manner as in Example 42, except that2-{4-[N-(5,6-di-p-tolyl-1,2,4-triazin-3-yl)-N-isopropylamino]butyloxy}aceticacid tert-butyl ester was used, the desired compound was prepared as ayellow crystal having a melting point of 119 to 121° C.

Elemental analysis (for C₂₆H₃₂N₄O₃) Calcd. (%): C, 69.62; H, 7.19; N,12.49. Found (%): C, 69.44; H, 7.15; N, 12.45.

EXAMPLE 49

2-{4-[N-(5,6-diphenyl-1,2,4-triazin-3-yl)-N-isopropylamino]butyloxy}aceticacid

In the same manner as in Example 47, except that2-{4-[N-(5,6-diphenyl-1,2,4-triazin-3-yl)-N-isopropylamino]butyloxy}aceticacid tert-butyl ester was used, the desired compound was prepared as ayellow crystal having a melting point of 128 to 130° C.

Elemental analysis (for C₂₄H₂₈N₄O₃) Calcd. (%): C, 68.55; H, 6.71; N,13.32. Found (%): C, 68.44; H, 6.64; N, 13.21.

EXAMPLE 50

2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acid

In the same manner as in Example 42, except that2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acidtert-butyl ester was used, the desired compound was prepared as a paleyellow crystal having a melting point of 161 to 162° C.

Elemental analysis (for C₂₅H₂₉N₃O₃) Calcd. (%): C, 71.58; H, 6.97; N,10.02. Found (%): C, 71.46; H, 6.97; N, 9.91.

EXAMPLE 51

2-[4-{N-[5,6-bis(4-methoxyphenyl)pyrazin-2-yl]-N-methylamino}butyloxy]aceticacid

In the same manner as in Example 42, except that2-{4-[N-[5,6-bis(4-methoxyphenyl)pyrazin-2-yl]-N-methylamino]butyloxy}aceticacid tert-butyl ester was used, the desired compound was prepared as apale yellow crystal having a melting point of 128 to 130° C.

Elemental analysis (for C₂₅H₂₉N₃O₅) Calcd. (%): C, 66.50; H, 6.47; N,9.31. Found (%): C, 66.42; H, 6.36; N, 9.18.

EXAMPLE 52

2-[4-{N-[5,6-bis(4-fluorophenyl)pyrazin-2-yl]-N-methylamino}butyloxy]aceticacid

In the same manner as in Example 42, except that2-[4-{N-[5,6-bis(4-fluorophenyl)pyrazin-2-yl]-N-methylamino}butyloxy]aceticacid tert-butyl ester was used, the desired compound was prepared as apale yellow crystal having a melting point of 116 to 118° C.

Elemental analysis (for C₂₃H₂₃F₂N₃O₃) Calcd. (%): C, 64.63; H, 5.42; N,9.83. Found (%): C, 64.76; H, 5.45; N, 9.61.

EXAMPLE 53

2-{4-[N-(5,6-diphenyl-3-methylpyrazin-2-yl)-N-methylamino]butyloxy}aceticacid sodium salt

After2-{4-[N-(5,6-diphenyl-3-methylpyrazin-2-yl)-N-methylamino]butyloxy}aceticacid tert-butyl ester was hydrolyzed in the same manner as in Example42, the resulting2-{4-[N-(5,6-diphenyl-3-methylpyrazin-2-yl)-N-methylamino]butyloxy}aceticacid was treated with the same amount of 1N sodium hydroxide solution toobtain the desired compound as a brownish amorphous.

Elemental analysis (for C₂₄H₂₆N₃O₃Na.0.4H₂O) Calcd. (%): C, 66.32; H,6.21; N, 9.67. Found (%): C, 66.59; H, 6.67; N, 9.63.

EXAMPLE 54

2-{2-[1-(5,6-diphenylpyrazin-2-yl)piperidin-4-yl]ethoxy}acetic acid

In the same manner as in Example 42, except that2-{2-[1-(5,6-diphenylpyrazin-2-yl)piperidin-4-yl]ethoxy}acetic acidtert-butyl ester was used, the desired compound was prepared as a paleyellow crystal having a melting point of 173 to 174° C.

Elemental analysis (for C₂₅H₂₇N₃O₃) Calcd. (%): C, 71.92; H, 6.52; N,10.06. Found (%): C, 71.62; H, 6.53; N, 9.79.

EXAMPLE 55

(±)-2-{3-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]propyloxy}aceticacid

In the same manner as in Example 42, except that(±)-2-{3-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]propyloxy}aceticacid tert-butyl ester was used, the desired compound was prepared as apale yellow crystal having a melting point of 137 to 139° C.

Elemental analysis (for C₂₅H₂₇N₃O₃) Calcd. (%): C, 71.92; H, 6.52; N,10.06. Found (%): C, 72.01; H, 6.56; N, 9.80.

EXAMPLE 56

2-{4-[N-(5,6-diphenyl-1,2,4-triazin-3-yl)-N-methylamino]butyloxy}aceticacid

In the same manner as in Example 47, except that2-{4-[N-(5,6-diphenyl-1,2,4-triazin-3-yl)-N-methylamino]butyloxy}aceticacid tert-butyl ester was used, the desired compound was prepared as ayellow crystal having a melting point of 108 to 110° C.

Elemental analysis (for C₂₂H₂₄N₄O₃) Calcd. (%): C, 67.33; H, 6.16; N,14.28. Found (%): C, 67.38; H, 6.22; N, 14.22.

EXAMPLE 57

(±)-2-{4-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]butyloxy}aceticacid

In the same manner as in Example 42, except that(±)-2-{4-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]butyloxy}aceticacid tert-butyl ester was used, the desired compound was prepared as apale yellow crystal having a melting point of 138 to 140° C.

Elemental analysis (for C₂₆H₂₉N₃O₃) Calcd. (%): C, 72.37; H, 6.77; N,9.74. Found (%): C, 72.35; H, 6.85; N, 9.50.

EXAMPLE 58

(±)-2-{2-[1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl]ethoxy}acetic acid

In the same manner as in Example 42, except that(±)-2-{2-[1-(5,6-diphenylpyrazin-2-yl)piperidin-3-yl]ethoxy}acetic acidtert-butyl ester was used, the desired compound was prepared as a paleyellow crystal having a melting point of 139 to 140° C.

Elemental analysis (for C₂₅H₂₇N₃O₃) Calcd. (%): C, 71.92; H, 6.52; N,10.06. Found (%): C, 71.99; H, 6.60; N, 10.00.

EXAMPLE 59

(R)-(+)-2-[3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-1-hydroxyethyl}phenoxy]aceticacid

In the same manner as in Example 42, except that(R)-2-[3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-1-hydroxyethyl}phenoxy]aceticacid methyl ester was used, the desired compound was prepared as a paleyellow crystal having a melting point of 158 to 159° C.

[α]D²⁰: +40.86 (c=0.465, methanol)

Elemental analysis (for C₂₇H₂₅N₃O₄) Calcd. (%): C, 71.19; H, 5.53; N,9.22. Found (%): C, 71.21; H, 5.58; N, 9.17.

EXAMPLE 60

2-[3-1[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}phenoxy]aceticacid

In the same manner as in Example 42, except that2-[3-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}phenoxy]aceticacid methyl ester was used, the desired compound was prepared as ayellowish crystal having a melting point of 182 to 187° C.

Elemental analysis (for C₂₆H₂₃N₃O₃) Calcd. (%): C, 73.39; H, 5.45; N,9.88. Found (%): C, 73.26; H, 5.47; N, 9.83.

EXAMPLE 61

2-[3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethyl}phenoxy]aceticacid

In the same manner as in Example 42, except that2-[3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethyl}phenoxy]aceticacid methyl ester was used, the desired compound was prepared as ayellowish crystal having a melting point of 174 to 176° C.

Elemental analysis (for C₂₇H₂₅N₃O₃) Calcd. (%): C, 73.79; H, 5.73; N,9.56. Found (%): C, 73.43; H, 5.79; N, 9.32.

EXAMPLE 62

4-(carboxymethoxy)-1-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]indane

In the same manner as in Example 42, except that1-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-4-(methoxycarbonylmethoxy)indanewas used, the desired compound was prepared as a pale yellow crystalhaving a melting point of 182 to 184° C.

Elemental analysis (for C₂₈H₂₅N₃O₃) Calcd. (%): C, 74.48; H, 5.58; N,9.31. Found (%): C, 74.06; H, 5.70; N, 9.09.

EXAMPLE 63

2-[4-(5,6-diphenylpyrazin-2-yloxy)butoxy]acetic acid sodium salt

Step 1

1-(5,6-diphenylpyrazin-2-yloxy)-4-(2-tetrahydropyranyloxy)butane

1.57 g of 4-(2-tetrahydropyranyloxy)-1-butanol was dissolved in 20 ml oftetrahydrofuran and 360 mg of 60% sodium hydride was added under icecooling, followed by stirring at room temperature for 1.5 hours. Themixture was refluxed for 30 minutes and ice-cooled again and 2.00 g of5-chloro-2,3-diphenylpyrazine was added. After stirring for 40 minutes,the mixture was heated to 80° C., stirred at the same temperature for4.5 hours and then stirred at room temperature for 88 hours. Thereaction solution was combined with ice water, extracted with ethylacetate and then washed with saturated brine. The extract was dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure to obtain 2.39 g of the desired compound as an oily substance.

Step 2

4-(5,6-diphenylpyrazin-2-yloxy)-1-butanol

2.39 g of1-(5,6-diphenylpyrazin-2-yloxy)-4-(2-tetrahydropyranyloxy)butane wasdissolved in methanol and 1.53 g of pyridium p-toluenesulfonate wasadded, and then the mixture was refluxed for 30 minutes. The reactionsolution was cooled, poured into ice water while stirring and thenextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressureto obtain 1.74 g of the desired compound as a colorless crystal having amelting point of 93 to 95° C.

Step 3

2-[4-(5,6-diphenylpyrazin-2-yloxy)butoxy]acetic acid sodium salt

500 mg of 4-(5,6-diphenylpyrazin-2-yloxy)-1-butanol was dissolved in 3ml of tert-butanol and 420 mg of potassium tert-butoxide was added, andthen a solution of 222 mg of chloroacetic acid in 1 ml of tert-butanolwas added under reflux. After 3 ml of tert-butanol was added, themixture was refluxed for 15 hours. After ice water was added and the pHwas adjusted to 4 using 1N hydrochloric acid, the reaction solution wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The resulting oily substance was dissolved in a solvent of benzene:methanol=4:1 and excess 2M trimethylsilyldiazomethane (hexane solution)was added to form a methyl ester. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to obtain 88 mg of an ester as an oily substance. Theester was dissolved in 1 ml of methanol and 1 ml of 1N sodium hydroxidesolution was added, followed by refluxing for one hour. After thesolvent was evaporated under reduced pressure, the residue was combinedwith water, washed with ethyl acetate, neutralized with 1 ml of 1Nhydrochloric acid and then extracted with ethyl acetate. The extract wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The resulting oily substance was dissolved inmethanol and the same amount of 1N sodium hydroxide solution was added,and then the solvent was evaporated under reduced pressure to obtain 60mg of the desired compound as a colorless amorphous.

Elemental analysis (for C₂₈H₂₅N₃O₃-1.1H₂O) Calcd. (%): C, 62.88; H,5.56; N, 6.67. Found (%): C, 63.07; H, 5.51; N, 6.28.

EXAMPLE 64

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acid

In the same manner as in Example 42, except that2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acidmethyl ester was used, the desired compound was prepared.

Elemental analysis (for C₂₃H₂₅N₃O₃) Calcd. (%): C, 70.57; H, 6.44; N,10.73. Found (%): C, 70.44; H, 6.42; N, 10.64.

EXAMPLE 65

7-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]heptanoic acid

In the same manner as in Example 42, except that7-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]heptanoic acid methylester was used, the desired compound was prepared as a colorless crystalhaving a melting point of 114 to 118° C.

Elemental analysis (for C₂₄H₂₇N₃O₂.0.2H₂O) Calcd. (%): C, 73.33; H,7.03; N, 10.69. Found (%): C, 73.32; H, 7.06; N, 10.41.

EXAMPLE 66

8-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]octanoic acid

In the same manner as in Example 42, except that8-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]octanoic acid methyl esterwas used, the desired compound was prepared as a colorless crystalhaving a melting point of 116 to 117° C.

Elemental analysis (for C₂₅H₂₉N₃O₂) Calcd. (%): C, 74.41; H, 7.24; N,10.41. Found (%): C, 74.16; H, 7.25; N, 10.29.

EXAMPLE 67

9-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]nonanoic acid

In the same manner as in Example 42, except that9-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]nonanoic acid methyl esterwas used, the desired compound was prepared as a colorless crystalhaving a melting point of 103 to 105° C.

Elemental analysis (for C₂₆H₃₁N₃O₂.0.3H₂O) Calcd. (%): C, 73.83; H,7.53; N, 9.93. Found (%): C, 73.80; H, 7.55; N, 9.65.

EXAMPLE 68

6-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]hexanoic acid

In the same manner as in Example 42, except that6-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]hexanoic acid ethyl esterwas used, the desired compound was prepared as a colorless crystalhaving a melting point of 159 to 160° C.

Elemental analysis (for C₂₃H₂₅N₃O₂) Calcd. (%): C, 73.58; H, 6.71; N,11.20. Found (%): C, 73.16; H, 6.82; N, 11.01.

EXAMPLE 69

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-ethylamino]butyloxy}acetic acidsodium salt

Using 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-ethylamino]butyloxy}aceticacid tert-butyl ester, carboxylic acid was formed in the same manner asin Example 42 and the resulting carboxylic acid was treated with thesame amount of 1N sodium hydroxide solution to obtain the desiredcompound as a pale yellow amorphous.

Elemental analysis (for C₂₄H₂₆N₃O₃Na.1H₂O) Calcd. (%): C, 64.71; H,6.34; N, 9.43. Found (%): C, 64.88; H, 6.25; N, 9.16.

EXAMPLE 70

2-{4-[N-allyl-N-(5,6-diphenylpyrazin-2-yl)aminolbutyloxy}acetic acidsodium salt

Using 2-{4-[N-allyl-N-(5,6-diphenylpyrazin-2-yl)amino]butyloxy}aceticacid tert-butyl ester, carboxylic acid was formed in the same manner asin Example 42 and the resulting carboxylic acid was treated with thesame amount of 1N sodium hydroxide solution to obtain the desiredcompound as a colorless amorphous.

Elemental analysis (for C₂₅H₂₆N₃O₃Na.0.7H₂O) Calcd. (%): C, 66.42; H,6.11; N, 9.29. Found (%): C, 66.31; H, 5.97; N, 8.98.

EXAMPLE 71

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(Z)-2-buten-1-yloxy]aceticacid

In the same manner as in Example 42, except that2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(Z)-2-buten-1-yloxy]aceticacid tert-butyl ester was used, the desired compound was prepared as apale yellow crystal having a melting point of 148 to 150° C.

Elemental analysis (for C₂₃H₂₃N₃O₃) Calcd. (%): C, 70.93; H, 5.95; N,10.79. Found (%): C, 70.71; H, 6.00; N, 10.67.

EXAMPLE 72

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(E)-2-buten-1-yloxy]aceticacid

In the same manner as in Example 42, except that2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(E)-2-buten-1-yloxy]aceticacid methyl ester was used, the desired compound was prepared as a paleyellow crystal having a melting point of 128 to 130° C.

Elemental analysis (for C₂₃H₂₃N₃O₃.0.2H₂O) Calcd. (%): C, 70.28; H,6.00; N, 10.69. Found (%): C, 70.33; H, 5.94; N, 10.46.

EXAMPLE 73

2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methylamino}pyrazine1-oxide

In the same manner as in Example 42, except that2,3-diphenyl-5-{N-[4-(tert-butoxycarbonylmethoxy)butyl]-N-methylamino}pyrazine1-oxide was used, the desired compound was prepared as a colorlesscrystal having a melting point of 185 to 190° C.

Elemental analysis (for C₂₃H₂₅N₃O₄) Calcd. (%): C, 67.80; H, 6.18; N,10.31. Found (%): C, 67.54; H, 6.18; N, 10.15.

EXAMPLE 74

2-{4-[N-(4,5-diphenylpyrimidin-2-yl)-N-methylamino]butyloxy}acetic acid

In the same manner as in Example 42, except that2-{4-[N-(4,5-diphenylpyrimidin-2-yl)-N-methylamino]butyloxy}acetic acidtert-butyl ester was used, the desired compound was prepared.

Elemental analysis (for C₂₃H₂₅N₃O₃) Calcd. (%): C, 70.57; H, 6.44; N,10.73. Found (%): C, 70.59; H, 6.42; N, 10.80.

EXAMPLE 75

2-{4-[N-(4,5-di-p-tolylpyrimidin-2-yl)-N-methylamino]butyloxy}aceticacid

In the same manner as in Example 42, except that2-{4-[N-(4,5-di-p-tolylpyrimidin-2-yl)-N-methylamino]butyloxy}aceticacid tert-butyl ester was used, the desired compound was prepared.

Elemental analysis (for C₂₅H₂₉N₃O₃) Calcd. (%): C, 71.58; H, 6.97; N,10.02. Found (%): C, 71.72; H, 6.96; N, 10.13.

EXAMPLE 76

2-{4-[(5,6-diphenylpyrazin-2-yl)thio]butyloxy}acetic acid

In the same manner as in Example 42, except that2-{4-[(5,6-diphenylpyrazin-2-yl)thio]butyloxy}acetic acid tert-butylester was used in place of2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acidtert-butyl ester, the desired compound was prepared as a pale yellowcrystal having a melting point of 86 to 88° C.

Elemental analysis (for C₂₂H₂₂N₂O₃S) Calcd. (%): C, 66.98; H, 5.62; N,7.10. Found (%): C, 66.81; H, 5.57; N, 7.47.

EXAMPLE 77

5-(carboxymethoxy)-2-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-1,2,3,4-tetrahydronaphthalene

In the same manner as in Example-42, except that5-(tert-butoxycarbonylmethoxy)-2-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-1,2,3,4-tetrahydronaphthalenewas used, the desired compound was prepared as a pale yellow crystalhaving a melting point of 212 to 213° C.

Elemental analysis (for C₃₀H₂₉N₃O₃.0.2H₂O) Calcd. (%): C, 74.57; H,6.13; N, 8.70. Found (%): C, 74.26; H, 6.19; N, 8.41.

EXAMPLE 78

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio]aceticacid sodium salt

Using2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio}aceticacid methyl ester, carboxylic acid was formed in the same manner as inExample 42 and the resulting carboxylic acid was treated with the sameamount of 1N sodium hydroxide solution to obtain the desired compound asa brownish amorphous.

Elemental analysis (for C₂₅H₂₈N₃O₂SNa.0.5H₂O) Calcd. (%): C, 64.36; H,6.26; N, 9.01. Found (%): C, 64.14; H, 6.05; N, 8.90.

EXAMPLE 79

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfinyl}aceticacid

In the same manner as in Example 42, except that2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfinyl]aceticacid methyl ester was used, the desired compound was prepared as ayellowish crystal having a melting point of 117 to 120° C. (withdecomposition).

Elemental analysis (for C₂₅H₂₉N₃O₃S) Calcd. (%): C, 66.49; H, 6.47; N,9.30. Found (%): C, 66.14; H, 6.47; N, 8.97.

EXAMPLE 80

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfonyl}aceticacid

In the same manner as in Example 42, except that2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfonyl]aceticacid methyl ester was used, the desired compound was prepared as ayellowish crystal having a melting point of 183 to 185° C.

Elemental analysis (for C₂₅H₂₉N₃O₄S.0.2H₂O) Calcd. (%): C, 63.73; H,6.29; N, 8.92. Found (%): C, 63.64; H, 6.23; N, 8.66.

EXAMPLE 81

2-[4-(5,6-diphenylpyrazin-2-sulfinyl)butyloxy]acetic acid sodium salt

In the same manner as in Example 47, except that2-[4-(5,6-diphenylpyrazin-2-sulfinyl)butyloxy]acetic acid tert-butylester was used, 2-[4-(5,6-diphenylpyrazin-2-sulfinyl)butyloxy]aceticacid was obtained as a pale yellow oily substance. 125 mg of theresulting oily substance was dissolved in methanol and, after adding0.30 ml of 1N sodium hydroxide solution, the solvent was evaporatedunder reduced pressure. The residue was solidified by adding isopropanoland diethyl ether, washed with diethyl ether and then dried to obtain 73mg of the desired compound as a pale yellow amorphous.

Elemental analysis (for C₂₂H₂₁N₂O₄SNa.1.5H₂O.0.5C₃H₈₀) Calcd. (%): C,57.66; H, 5.76; N, 5.72. Found (%): C, 58.30; H, 5.10; N, 5.45.

EXAMPLE 82

2-[4-(5,6-diphenylpyrazin-2-sulfonyl)butyloxy]acetic acid

In the same manner as in Example 47, except that2-[4-(5,6-diphenylpyrazin-2-sulfonyl)butyloxy]acetic acid tert-butylester was used, the desired compound was prepared as a pale yellowcrystal having a melting point of 123 to 125° C.

Elemental analysis (for C₂₂H₂₂N₂O₅S) Calcd. (%): C, 61.96; H, 5.20; N,6.57. Found (%): C, 61.95; H, 5.25; N, 6.41.

EXAMPLE 83

2-[5-(5,6-diphenylpyrazin-2-yl)pentyloxy]acetic acid sodium salt

In the same manner as in Example 42, except that2-[5-(5,6-diphenylpyrazin-2-yl)pentyloxy]acetic acid tert-butyl esterwas used in place of2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acidtert-butyl ester, 2-[5-(5,6-diphenylpyrazin-2-yl)pentyloxy]acetic acidwas obtained as an oily substance. The resulting oily substance wastreated with the same amount of 1N sodium hydroxide solution to obtainthe desired compound as a pale brown amorphous.

Elemental analysis (for C₂₃H₂₃N₂O₃Na.0.5H₂O) Calcd. (%): C, 67.80; H,5.94; N, 6.88. Found (%): C, 68.03; H, 6.22; N, 6.48.

EXAMPLE 84

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide

Under an argon atmosphere, to a solution of 300 mg of2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acidobtained in Example 42 in 5 ml of anhydrous tetrahydrofuran, 128 mg of1,1′-carbonyl diimidazole was added and, after stirring at roomtemperature for 30 minutes, the mixture was heated at reflux for 30minutes. After air-cooling to room temperature, 69 mg ofmethanesulfonamide was added. After stirring for 10 minutes, 0.11 ml of1,8-diazabicyclo[5.4.0.]-7-undecene was added dropwise. After stirringat room temperature overnight, the reaction solution was diluted withwater and then extracted with diethyl ether. The extract was dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure, and then the residue was purified by silica gel columnchromatography to obtain 272 mg of the desired compound.

Elemental analysis (for C₂₆H₃₂N₄O₄S) Calcd. (%): C, 62.88; H, 6.49; N,11.28. Found (%): C, 63.06; H, 6.47; N, 10.98.

EXAMPLE 85

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(p-toluenesulfonyl)acetamide

To a solution of 500 mg of2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acidobtained in Example 42 in 5 ml of anhydrous tetrahydrofuran, 214 mg of1,1′-carbonyldiimidazole was added and, after stirring at roomtemperature for 30 minutes, the mixture was heated at reflux for 30minutes. After air-cooling to room temperature, 206 mg ofp-toluenesulfonamide was added. After stirring for 10 minutes, 0.18 mlof 1,8-diazabicyclo[5.4.0.]undec-7-ene was added dropwise. Afterstirring at room temperature overnight, almost all of the solvent wasevaporated under reduced pressure. The residue was combined with waterand then neutralized with 1N hydrochloric acid. The reaction solutionwas extracted with ethyl acetate and dried over anhydrous magnesiumsulfate, the solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography to obtain 460 mg of thedesired compound.

Elemental analysis (for C₃₂H₃₆N₄O₄S) Calcd. (%): C, 67.11; H, 6.34; N,9.78. Found (%): C, 67.04; H, 6.37; N, 9.65.

EXAMPLE 86

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(isopropylsulfonyl)acetamide

In the same manner as in Example 85, except that isopropylsulfonamidewas used in place of p-toluenesulfonamide, the desired compound wasprepared.

Elemental analysis (for C₂₈H₃₆N₄O₄S) Calcd. (%): C, 64.10; H, 6.92; N,10.68. Found (%): C, 64.19; H, 6.97; N, 10.62.

EXAMPLE 87

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(trifluoromethanesulfonyl)acetamide

In the same manner as in Example 85, except thattrifluoromethanesulfonamide was used in place of p-toluenesulfonamide,the desired compound was prepared.

Elemental analysis (for C₂₆H₂₉F₃N₄O₄S.1.2H₂O) Calcd. (%): C, 54.57; H,5.53; N, 9.79. Found (%): C, 54.41; H, 5.22; N, 9.45.

EXAMPLE 88

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(o-toluenesulfonyl)acetamide

In the same manner as in Example 85, except that o-toluenesulfonamidewas used in place of p-toluenesulfonamide, the desired compound wasprepared.

Elemental analysis (for C₃₂H₃₆N₄O₄S) Calcd. (%): C, 67.11; H, 6.34; N,9.78. Found (%): C, 66.95; H, 6.32; N, 9.59.

EXAMPLE 89

N-(benzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide

In the same manner as in Example 85, except that benzenesulfonamide wasused in place of p-toluenesulfonamide, the desired compound wasprepared.

Elemental analysis (for C₃₁H₃₄N₄O₄S) Calcd. (%): C, 66.64; H, 6.13; N,10.03. Found (%): C, 66.66; H, 6.12; N, 9.99.

EXAMPLE 90

N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide

In the same manner as in Example 85, except that4-chlorobenzenesulfonamide was used in place of p-toluenesulfonamide,the desired compound was prepared.

Elemental analysis (for C₃₁H₃₃ClN₄O₄S) Calcd. (%): C, 62.77; H, 5.61; N,9.45. Found (%): C, 62.99; H, 5.58; N, 9.50.

EXAMPLE 91

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-methoxybenzenesulfonyl)acetamide

In the same manner as in Example 85, except that4-methoxybenzenesulfonamide was used in place of p-toluenesulfonamide,the desired compound was prepared.

Elemental analysis (for C₃₂H₃₆N₄O₅S.0.6H₂O) Calcd. (%): C, 64.11; H,6.25; N, 9.35. Found (%): C, 63.86; H, 5.95; N, 9.39.

EXAMPLE 92

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-fluorobenzenesulfonyl)acetamide

In the same manner as in Example 85, except that4-fluorobenzenesulfonamide was used in place of p-toluenesulfonamide,the desired compound was prepared.

Elemental analysis (for C₃₁H₃₃FN₄O₄S) Calcd. (%): C, 64.56; H, 5.77; N,9.72. Found (%): C, 64.36; H, 5.88; N, 9.56.

EXAMPLE 93

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(2-thiophenesulfonyl)acetamide

In the same manner as in Example 85, except that 2-thiophenesulfonamidewas used in place of p-toluenesulfonamide, the desired compound wasprepared.

Elemental analysis (for C₂₉H₃₂N₄O₄S₂) Calcd. (%): C, 61.68; H, 5.71; N,9.92. Found (%): C, 61.70; H, 5.78; N, 9.76.

EXAMPLE 94

N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide

In the same manner as in Example 85, except that sulfamide was used inplace of p-toluenesulfonamide, the desired compound was prepared.

Elemental analysis (for C₂₅H₃₁N₅O₄S) Calcd. (%): C, 60.34; H, 6.28; N,14.07. Found (%): C, 60.09; H, 6.27; N, 14.04.

EXAMPLE 95

N-(N,N-dimethylaminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide

In the same manner as in Example 85, except that N,N-dimethylsulfamidewas used in place of p-toluenesulfonamide, the desired compound wasprepared.

Elemental analysis (for C₂₇H₃₅N₅O₄S) Calcd. (%): C, 61.69; H, 6.71; N,13.32. Found (%): C, 61.60; H, 6.64; N, 13.24.

EXAMPLE 96

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(morpholin-4-ylsulfonyl)acetamide

In the same manner as in Example 85, except thatmorpholin-4-ylsulfonamide was used in place of p-toluenesulfonamide, thedesired compound was prepared.

Elemental analysis (for C₂₉H₃₇N₅O₅S) Calcd. (%): C, 61.36; H, 6.57; N,12.34. Found (%): C, 61.11; H, 6.59; N, 12.03.

EXAMPLE 97

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(pyrrolidin-1-ylsulfonyl)acetamide

In the same manner as in Example 85, except thatpyrrolidin-1-ylsulfonamide was used in place of p-toluenesulfonamide,the desired compound was prepared.

Elemental analysis (for C₂₉H₃₇N₅O₄S) Calcd. (%): C, 63.13; H, 6.76; N,12.69. Found (%): C, 63.11; H, 6.78; N, 12.49.

EXAMPLE 98

[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamicacid phenyl ester

In the same manner as in Example 85, except that sulfamic acid phenylester was used in place of p-toluenesulfonamide, the desired compoundwas prepared.

Elemental analysis (for C₃₁H₃₄N₄O₅S) Calcd. (%): C, 64.79; H, 5.96; N,9.75. Found (%): C, 64.93; H, 6.01; N, 9.59.

EXAMPLE 99

2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide

1.50 g of2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acidwas dissolved in 20 ml of anhydrous tetrahydrofuran and 0.500 ml oftriethylamine was added and then 0.376 ml of ethyl chlorocarbonate wasadded while stirring under ice cooling. After stirring under ice coolingfor 45 minutes, a solution of saturated ammonia in 20 ml oftetrahydrofuran was added, followed by stirring for one hour. Afterremoving an ice bath and stirring at room temperature for 18 hours,almost all of the solvent was evaporated. The residue was combined withwater and then extracted with ethyl acetate. The extract was washed inturn with an aqueous saturated sodium hydrogen carbonate solution, 1Nsodium hydroxide solution and water and dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressure. Theresidue was washed with diethyl ether and then dried under reducedpressure to obtain 1.19 g of the desired product.

Elemental analysis (for C₂₅H₃₀N₄O₂) Calcd. (%): C, 71.74; H, 7.22; N,13.39. Found (%): C, 71.79; H, 7.30; N, 13.34.

EXAMPLE 100

N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamicacid sodium salt

Under an argon atmosphere, a solution of 1.443 g of 2-picoline in 1.7 mlof 1,2-dichloroethane was cooled to −10° C. A solution of chlorosulfonicacid in 3.5 ml of 1,2-dichloroethane was added dropwise at 0° C. orlower and, after stirring for 15 minutes, 712 mg of2-[4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy]acetamidewas added. The reaction solution was heated to 75° C. and air-cooled toroom temperature after stirring for 2 hours. The reaction solution wasdiluted with dichloromethane and then washed in turn with an aqueous0.6M sodium hydrogen sulfate and water. The reaction solution was driedover anhydrous magnesium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform-methanol) to obtain 798 mg ofN-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamicacid.

Elemental analysis (for C₂₅H₃₀N₄O₅SN.0.5CHCl₃) Calcd. (%): C, 54.86; H,5.51; N, 10.04. Found (%): C, 54.72; H, 5.51; N, 9.84.

EXAMPLE 101

100 mg of the compound obtained in Example 100 was dissolved in 1 ml ofa mixed solution of ethanol and water (1:1) and 0.200 ml of a 1N sodiumhydroxide solution was added. After the solvent was evaporated, themixture was solidified with a mixed solution of ethanol and methanol andthe solid was collected by filtration and then dried under reducedpressure to obtain 49 mg of the titled compound as a colorless solid.

Elemental analysis (for C₂₅H₂₉N₄O₅SNa.1.5H₂O) Calcd. (%): C, 54.83; H,5.89; N, 10.23. Found (%): C, 54.39; H, 5.48; N, 10.07.

TEST EXAMPLE 1

Human Platelet Aggregation Inhibition Test

Blood collected from healthy human volunteers into aqueous trisodiumcitrate solution was centrifuged at 200×g for 10 minutes and the upperlayer was recovered to obtain platelet-rich plasma (PRP). The residualblood containing trisodium citrate added therein was centrifuged at1500×g for 10 minutes and the supernatant was collected as platelet-poorplasma (PPP). The number of platelets in the PRP was adjusted to about300,000/μl by PPP. Platelet aggregation was measured by an aggregometer.180 μl of PRP was added to cuvettes and incubated at 37° C. for oneminute, and then 10 μl of test compound solution (prepared by dissolvinga test compound with a 1.5-fold mole of a sodium hydroxide solution anddiluting with water) was added and the mixture was further incubated for2 minutes. Then, 10 μl of aqueous adenosine diphosphate (ADP) solutionwas added to adjust the final concentration as 1×10⁻⁵ M and plateletaggregation was induced and observed for 7 minutes. Inhibitionpercentage of aggregation was calculated from the percentage ofaggregation upon the addition of the test compound to the percentage ofaggregation upon the addition of water in place of the test compoundsolution (control). The test compound was added to adjust the finalconcentration to the range from 10⁻⁸ to 10⁻⁴ M, and IC₅₀ values weredetermined by inhibition percentage of aggregation at eachconcentration. The results are shown in Table 1.

It is apparent that the compounds of the present invention markedlyinhibit platelet aggregation in human PRP.

TABLE 1 Inhibition of human platelet aggregation Test compounds IC₅₀(μM) Example 42 0.2 Example 43 0.8 Example 46 0.5 Example 48 0.4 Example64 0.2 Example 65 0.3 Example 73 0.2 Example 74 0.8 Example 75 0.2Example 78 0.3

TEST EXAMPLE 2

³H-Iloprost Binding Inhibition Test to Human Platelet Membrane

Human platelet membrane of 100 μg protein was suspended in 200 μl of 50mM Tris-HCl buffer (pH7.4) containing 10 mM MgCl₂, 1 mM EGTA and 5 nM³H-Iloprost and then incubated at 37° C. for 10 minutes with 5 μMnon-labeled Iloprost or the compound (1 μM) of Example 64. The plateletmembrane was collected on a glass filter and its radioactivity wasmeasured after washing four times with 50 mM Tris-HCl buffer. Thecompound (1 μM) of Example 64 inhibited binding of ³H-Iloprost by 85%.

TEST EXAMPLE 3

Increase in cAMP in Human Platelet

500 μl of washed human platelet suspension (2×10⁸/ml) containing eachconcentration of the compound of Example 64 was incubated at 37° C. for10 minutes and sonicated after adding aqueous 1 M perchloric acidsolution. After the sonicated solution was centrifuged and thesupernatant was neutralized with an aqueous 1 M potassium hydrogencarbonate solution, centrifuged again and the supernatant was recovered.The concentration of cAMP in the supernatant was determined by an ELISAmethod. As shown in Table 2, the amount of cAMP in platelets wasincreased by the compound of Example 64 in a concentration-dependentmannar.

TABLE 2 Increase in cAMP in human platelet. Concentration of cAMPExample 64 (nM) (pmol/10⁸ platelet) 10 3.7 30 6.4 100 20.7 300 28.5 100039.4 3000 35.3

As is apparent from Test Examples 1 to 3, the compounds of the presentinvention inhibit platelet aggregation on the basis of their PGI₂receptor antagonistic activity.

TEST EXAMPLE 4

Singl-Dose Toxicity Test in Mice

The compound of Example 42 was orally administered to mice (includingthree mice in a group) at a dose of 10, 30 or 100 mg/kg. As a result,there were no deaths.

The compound of Example 64 was orally administered to mice (includingfive mice in a group) at a dose of 300 mg/kg. As a result, there were nodeaths.

TEST EXAMPLE 5

Ex Vivo Platelet Aggregation Inhibition Test in Monkeys

Method

The compound of Example 84 was orally administered to two cynomolgusmonkeys (Macaca fascicularis, male, aged 3 to 5) at a dose of 0.3 or 1mg/kg. Before the administration or 2, 4 and 8 hours after theadministration, blood (each 4.5 ml) was collected using an injectioncylinder containing aqueous 3.8% citric acid solution in the amount of1/10 of the volume of blood to be collected. Blood containing citricacid solution was centrifuged at 200×g for 10 minutes and the upperlayer was collected as PRP. Furthermore, the residual blood wascentrifuged at 1500×g for 10 minutes and the supernatant was collectedas PPP. 190 μl of PRP was added to a cuvette and incubated at 37° C. forone minute, and then 10 μl of ADP solution (5 to 30 μM) was added toinduce platelet aggregation. The percentage of platelet aggregation wasmeasured by an aggregometer (PM8C, Mebanix, Tokyo) using PPP as theblank and inhibition percentage of platelet aggregation was determinedby comparing the percentage of aggregation before administration of thecompound with the percentage of aggregation after administration of thecompound according to the following equation. The results are shown inTable 3.Inhibition percentage of Platelet Aggregation (%)=100−(The percentage ofAggregation after administration of compound)/(The percentage ofAggregation before administration of compound)×100

TABLE 3 Inhibition percentage of platelet aggregation in monkeys (%)Time after Dose of Example 84 administration (mg/kg) (h) 0.3 1 2 28 63 434 40 8 19 52

It is apparent that the compound of Example 84 inhibits plateletaggregation persistently in a dose-dependent manner after 2 to 8 hourshave passed since the administration, and drug efficacy persists for along time.

FORMULATION EXAMPLE 1

Tablets (tablets for internal use)

Formulation weighing 200 mg per tablet

Compound of Example 40 20 mg Corn starch 88 mg Crystalline cellulose 80mg Calcium Carboxymethylcellulose 10 mg Light anhydrous silicic acid  1mg Magnesium stearate  1 mg

Mixed powders prepared according to the above formulation werecompressed to give tablets for internal use.

FORMULATION EXAMPLE 2

Tablets (tablets for internal use)

Formulation weighting 120 mg per tablet

Compound of Example 51  1 mg Lactose 60 mg Corn starch 30 mg Crystallinecellulose 20 mg Hydroxypropylcellulose  7 mg Magnesium stearate  2 mg

Mixed powders prepared according to the above formulation werecompressed to give tablets for internal use.

FORMULATION EXAMPLE 3

Tablets (tablets for internal use)

Formulation weighing 180 mg per tablet

Compound of Example 63 100 mg Lactose  45 mg Corn starch  20 mg Lowsubstituted hydroxypropylcellulose  9 mg Polyvinyl alcohol (partiallysaponified)  5 mg Magnesium stearate  1 mg

Mixed powders prepared according to the above formulation werecompressed to give tablets for internal use.

INDUSTRIAL APPLICABILITY

The compound of the present invention is useful as a therapeutic agentsuch as platelet coagulation inhibitor because it has a PGI₂ receptorantagonistic activity and also has low toxicity.

1. A pharmaceutical composition comprising a heterocyclic compoundrepresented by the following general formula (1) or a salt thereof as anactive ingredient:

wherein R¹ and R² are the same or different and each represents anoptionally substituted aryl, and the substituents are the same ordifferent and 1 to 3 substituents are selected from the group consistingof halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl,alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy,cyano and nitro, Y represents N or N→O, Z represents CR⁶; and R⁶represents hydrogen, alkyl, or halogen, A represents NR⁷ or SO, and R⁷represents hydrogen, alkyl, alkenyl or cycloalkyl, D represents alkyleneor alkenylene which are optionally substituted with hydroxy, or A and Dare combined with each other to form a divalent group represented by thefollowing formula (2):

r represents an integer of 0 to 2, q represents an integer of 2 to 3,and t represents an integer of 0 to 4, E represents phenylene or singlebond, or D and E are combined with each other to form a divalent grouprepresented by the following formula (3):

u represents an integer of 0 to 2, and v represents 0 or 1, G representsO, S, SO, SO₂, or C(R⁸)(R⁹), and R⁸ and R⁹ are the same or different andeach represents hydrogen or alkyl, R³ and R⁴ are the same or differentand each represents hydrogen or alkyl, Q represents carboxy,alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl,dialkylcarbamoyl, or a group represented by the following formula (22):

R¹⁰ represents amino, monoalkylamino, dialkylamino, hydroxy, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaryloxy, or optionally substituted heterocyclic group, and thesubstituents of alkyl, aryl, aryloxy or heterocyclic group are the sameor different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro; and a pharmaceuticallyacceptable carrier.
 2. The pharmaceutical composition according to claim1, wherein, in the formula (1), R¹ and R² are the same or different andeach represents optionally substituted phenyl, and the substituents arethe same or different and 1 to 3 substituents are selected from thegroup consisting of halogen, alkyl and alkoxy, Y and Z correspond toeither of the following cases (1) and (2): (1) Y is N, and Z is CH, and(2) Y is N→O, and Z is CH, A represents NR⁷, and R⁷ represents hydrogen,alkyl, or cycloalkyl, D represents alkylene or alkenylene, E representssingle bond, G represents O, S, SO, SO₂, or C(R⁸)(R⁹), and R⁸ and R⁹each represents hydrogen, R³ and R⁴ are the same or different and eachrepresents hydrogen or alkyl, and Q represents carboxy, alkoxycarbonyl,tetrazolyl, or a group represented by the formula (22), and R¹⁰represents amino, monoalkylamino, dialkylamino, hydroxy, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaryloxy, or optionally substituted heterocyclic group, and thesubstituents of alkyl, aryl, aryloxy or heterocyclic group are the sameor different and 1 to 3 substituents selected from the group consistingof halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl,alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy,cyano and nitro.
 3. The pharmaceutical composition according to claim 1,wherein, in the formula (1), R¹ and R² are the same or different andeach represents optionally substituted phenyl, and the substituents arethe same or different and 1 to 3 substituents are selected from thegroup consisting of halogen, alkyl and alkoxy, Y is N, and Z is CH, Arepresents NR⁷, and R⁷ represents hydrogen or alkyl, D representsalkylene, E represents single bond, G represents O, R³ and R⁴ are thesame or different and each represents hydrogen or alkyl, Q representscarboxy, tetrazolyl, or a group represented by the formula (22), and R¹⁰represents amino, monoalkylamino, dialkylamino, hydroxy, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaryloxy, or optionally substituted heterocyclic group, and thesubstituents of alkyl, aryl, aryloxy or heterocyclic group are the sameor different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro.
 4. The pharmaceuticalcomposition according to claim 1, wherein, in the formula (1), R¹ and R²are the same or different and each represents optionally substitutedphenyl, and the substituents are the same or different and 1 to 3substituents are selected from the group consisting of halogen, alkyland alkoxy, Y represents N, and Z represents CH, A represents NR⁷, andR⁷ represents alkyl, D represents alkylene, E represents single bond, Grepresents O, R³ and R⁴ are the same or different and each representshydrogen or alkyl, and Q represents carboxy or a group represented bythe formula (22), and R¹⁰ represents amino monoalkylamino, dialkylamino,hydroxy, optionally substituted alkyl, optionally substituted aryl,optionally substituted aryloxy or optionally substituted heterocyclicgroup, and the substituents of alkyl, aryl, aryloxy or heterocyclicgroup are the same or different and 1 to 3 substituents are selectedfrom the group consisting of halogen, alkyl, haloalkyl, arylalkyl,alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino,monoalkylamino, dialkylamino, carboxy, cyano and nitro.
 5. Thepharmaceutical composition according to claim 1, wherein the heterocyclic compound is selected from the group consisting of the followingcompounds (1) to (27): (1)2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acid,(2) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]butyloxy}aceticacid, (3)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}aceticacid, (4)2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-isopropylamino]butyloxy}aceticacid, (5)2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methylamino}pyrazine1-oxide, (6) 7-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]heptanoicacid, (7)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio}aceticacid, (8)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(Z)-2-buten-1-yloxy}aceticacid, (9)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-ethylamino]butyloxy}acetic acid,(10)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfinyl}aceticacid, (11)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(p-toluenesulfonyl)acetamide,(12)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(isopropylsulfonyl)acetamide,(13)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(trifluoromethanesulfonyl)acetamide,(14)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(o-toluenesulfonyl)acetamide,(15)N-(benzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,(16)N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,(17)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-methoxybenzenesulfonyl)acetamide,(18)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-fluorobenzenesulfonyl)acetamide,(19)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(2-thiophenesulfonyl)acetamide,(20)N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,(21)N-(N,N-dimethylaminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,(22)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(morpholin-4-ylsulfonyl)acetamide,(23)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(pyrrolidin-1-ylsulfonyl)acetamide,(24)N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamicacid phenyl ester, (25)N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamicacid, (26)N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamicacid sodium salt, and (27)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.6. A method of inhibiting platelet aggregation, comprising administeringto a subject in need thereof an effective amount of a pharmaceuticalcomposition according to claim
 1. 7. A method of treatingarteriosclerosis obliterans, comprising administering to a subject inneed thereof an effective amount of a pharmaceutical compositionaccording to claim
 1. 8. A method of treating intermittent claudication,comprising administering to a subject in need thereof an effectiveamount of a pharmaceutical composition according to claim
 1. 9. A methodof treating peripheral arterial embolism, comprising administering to asubject in need thereof an effective amount of a pharmaceuticalcomposition according to claim
 1. 10. A heterocyclic compoundrepresented by the following general formula (1z) or a salt thereof:

wherein: R⁹¹ and R⁹² are the same or different and each representsoptionally substituted aryl, and the substituents are the same ordifferent and 1 to 3 substituents are selected from the group consistingof halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl,alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy,cyano and nitro, Y⁹ represents N or N→O, Z⁹ represents CR⁹⁶, and R⁹⁶represents hydrogen, alkyl, or halogen, A⁹ represents NR⁹⁷ or SO, andR⁹⁷ represents hydrogen, alkyl, alkenyl, or cycloalkyl, D⁹ representsalkylene or alkenylene which are optionally substituted with bydroxy, orA⁹ and D⁹ are combined with each other to form a divalent grouprepresented by the following formula (2z):

m represents an integer of 0 to 2, k represents an integer of 2 to 3,and n represents an integer of 0 to 4, E⁹ represents phenylene or singlebond, or D⁹ and E⁹ are combined with each other to form a divalent grouprepresented by the following formula (3z):

w represents an integer of 0 to 2, and x represents 0 or 1, G⁹represents O, S, SO, SO₂, or C(R⁹⁸)(R⁹⁹), and R⁹⁸ and R⁹⁹ are the sameor different and each represents hydrogen or alkyl, R⁹³ and R⁹⁴ are thesame or different and each represents hydrogen or alkyl, Q⁹ representscarboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl,dialkylcarbamoyl, or a group represented by the following formula (22z):

R⁹¹⁰ represents amino, monoalkylamino, dialkylaxuino, hydroxy,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted aryloxy, or optionally substituted heterocyclic group, andthe substituents of alkyl, aryl, aryloxy or heterocyclic group are thesame or different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro.
 11. The heterocyclic compoundaccording to claim 10, wherein, in the formula (1z), substituentscorrespond to the following case: R⁹¹ and R⁹² are the same or differentand each represents optionally substituted phenyl, and the substituentsare the same or different and 1 to 3 substituents are selected from thegroup consisting of halogen, alkyl and. alkoxy, Y⁹ and Z⁹correspond toeither of the following cases (1) and (2): (1) Y⁹ is N, and Z⁹ is CH,and (2) Y⁹ is N→O, and Z⁹ is CH, A⁹ represents NR⁹⁷, and R⁹⁷ representshydrogen, alkyl, or cycloalkyl, D⁹ represents alkylene, E⁹ single bond,G⁹ represents O, S. SO, SO₂, or C(R⁹⁸)(R⁹⁹), and R⁹⁸ and R⁹⁹ eachrepresents hydrogen, R⁹³ and R⁹⁴ are the same or different and eachrepresents hydrogen or alkyl, and Q⁹ represents carboxy, alkoxycarbonyl,tetrazolyl, or a group represented by the formula (22z), R⁹¹⁰ representsamino, monoalkylarnino, dialkylamino, hydroxy, optionally substitutedalkyl, optionally substituted aryl, optionally substituted aryloxy, oroptionally substituted heterocyclic group, and the substituents ofalkyl, aryl, aryloxy or heterocyclic group are the same or different and1 to 3 substituents are selected from the group consisting of halogen,alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl,alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy,cyano and nitro.
 12. The heterocyclic compound according to claim 10,wherein, in the formula (1z), R⁹¹ and R⁹² are the same or different andeach represents optionally substituted phenyl, and the substituents arethe same or different and 1 to 3 substituents are selected from thegroup consisting of halogen, alkyl and alkoxy, Y⁹ represents N, Z⁹represents CH, A⁹ represents NR⁹⁷, and R⁹⁷ represents hydrogen or alkyl,D⁹ represents alkylene, E⁹ represents single bond, G⁹ represents O, R⁹³and R⁹⁴ are the same or different and each represents hydrogen or alkyl,Q⁹ represents carboxy, tetrazolyl, or a group represented by the formula(22z), R⁹¹⁰ represents amino, monoalkylamino, dialkylamino, hydroxy,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted aryloxy, or optionally substituted heterocyclic group, andthe substituents of alkyl, aryl, aryloxy or heterocyclic group are thesame or different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro.
 13. The heterocyclic compoundaccording to claim 10, wherein R⁹¹ and R⁹² are the same or different andeach represents optionally substituted phenyl, and the substituents arethe same or different and 1 to 3 substituents are selected from thegroup consisting of halogen, alkyl and alkoxy, Y⁹ represents N, and Z⁹represents CH, A⁹ represents NR⁹⁷, and R⁹⁷ represents alkyl, D⁹represents alkylene, E⁹ single bond, G⁹ represents O, R⁹³ and R⁹⁴ arethe same or different and each represents hydrogen or alkyl, Q⁹represents carboxy or a group represented by the formula (22z), R⁹¹⁰represents amino, monoalkylamino, dialkylamino, hydroxy, optionallysubstituted alkyl, optionally substituted aryl, optionaiiy substitutedaryloxy, or optionally substituted heterocyclic group, and thesubstitunets of alkyl, aryl, aryloxy or heterocyclic group are the sameor different and 1 to 3 substituents are selected from the groupconsisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio,alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino,dialkylamino, carboxy, cyano and nitro.
 14. The heterocyclic compoundaccording to claim 10, wherein the heterocyclic compound is selectedfrom the following compounds (1) to (27): (1)2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acid,(2) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]butyloxy}aceticacid, (3)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}aceticacid, (4)2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-isopropylamino]butyloxy}aceticacid, (5)2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methylamino}pyrazine1-oxide, (6) 7-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]heptanoicacid, (7)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio}aceticacid, (8)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(Z)-2-buten-1-yloxy}aceticacid, (9)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-ethylamino]butyloxy}acetic acid,(10)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfinyl}aceticacid, (11)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(p-toluenesulfonyl)acetamide,(12)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(isopropylsulfonyl)acetamide,(13)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(trifluoromethanesulfonyl)acetamide,(14)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(o-toluenesulfonyl)acetamide,(15)N-(benzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,(16)N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,(17)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-methoxybenzenesulfonyl)acetamide,(18)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-fluorobenzenesulfonyl)acetamide,(19)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(2-thiophenesulfonyl)acetamide,(20)N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,(21)N-(N,N-dimethylaminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide,(22)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(morpholin-4-ylsulfonyl)acetamide,(23)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(pyrrolidin-1-ylsulfonyl)acetamide,(24)N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamicacid phenyl ester, (25)N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamicacid, (26)N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamicacid sodium salt, and (27)2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.15. A method of treating pulmonary hypertension, comprisingadministering to a subject in need thereof an effective amount of apharmaceutical composition according to claim 1.